Treatment of cns disorders using cns target modulators

ABSTRACT

The invention is directed to compositions used for treating Central Nervous System (CNS) disorders. In addition, the invention provides convenient methods of treatment of a CNS disorder. Furthermore, the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of derivatized, e.g., ester or carboxylic acid derivatized, antihistamine antagonists for the treatment of sleep disorders.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Attorney Docket Number HPZ-001-1, Application Ser. No.60/329,701, filed on Oct. 16, 2001, entitled “Treatment of CNS DisordersUsing CNS Target Modulators”; pending U.S. Provisional PatentApplication Attorney Docket Number HPZ-001-2, Application Ser. No.60/381,507, filed on May 17, 2002, entitled “Treatment of CNS DisordersUsing CNS Target Modulators”; pending U.S. Provisional PatentApplication Attorney Docket Number HPZ-001-3, filed on Sep. 27, 2002,entitled “Treatment of CNS Disorders' Using CNS Target Modulators”; andpending U.S. Provisional Patent Application Attorney Docket NumberHPZ-001-4, filed on even date herewith, entitled “Treatment of CNSDisorders Using CNS Target Modulators” the entire contents of each ofthe above-identified applications, which are hereby incorporated hereinby reference.

BACKGROUND OF THE INVENTION

Difficulties in falling asleep, remaining asleep, sleeping for adequatelengths of time, or abnormal sleep behavior are common symptoms forthose suffering with a sleep disorder. A number of sleep disorders,e.g., insomnia or sleep apnea, are described in the online Merck Manualof Medicinal Information.

Current treatment of many sleep disorders include the use ofprescription hypnotics, e.g., benzodiazapines, that may behabit-forming, lose their effectiveness after extended use, andmetabolize more slowly for certain designated groups, e.g., elderlypersons, resulting in persisting medicative effects.

Other, more mild manners of treatment include over-the-counterantihistamines, e.g., diphenhydramine or dimenhydrinate, which are notdesigned to be strictly sedative in their activity. This method oftreatment is also associated with a number of adverse side effects,e.g., persistence of the sedating medication after the prescribed timeof treatment, or the so-called “hangover effect”. Many of these sideeffects result from nonspecific activity in both the periphery as wellas the Central Nervous System (CNS) during this period of extendedmedication.

SUMMARY OF THE INVENTION

A need exists for the development of new compositions used for theimproved treatment of sleep disorders that remain active for a discreteperiod of time to reduce side effects, such as the “hangover effect.”The strategy of treatment is applicable to a broader array of CNStargets.

Therefore, the invention is directed to compositions used for treatingCentral Nervous System (CNS) disorders. In addition, the inventionprovides convenient methods of treatment of a CNS disorder. Furthermore,the invention provides methods of treating sleep disorders usingcompositions that remain active for a discrete period of time to reduceside effects. More specifically, the invention is directed to thecompositions and use of derivatized, e.g., ester or carboxylic acidderivatized, antihistamine antagonists for the treatment of sleepdisorders.

Thus, in one aspect of the invention, the invention is a method oftreating a sleep disorder. The method comprises administering aneffective amount of an antihistamine compound, such that the sleepdisorder is treated, wherein the antihistamine compound has a favorablebiological property (FBP).

An additional aspect of the invention is a method of treating a CentralNervous System (CNS) disorder. The method comprises administering aneffective amount of a therapeutic compound to a subject, such that thetherapeutic compound penetrates into the CNS and modulates the CNStarget to treat the CNS disorder. Accordingly, the therapeutic compoundcan have the formula:[CA]−(SP)_(n) −[DA]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, DA is a drug activitymodulating moiety that provides the ability to modulate the activity ofthe therapeutic compound, e.g., ester or carboxylic acid, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a method of treating a CentralNervous System (CNS) disorder. The method comprises administering aneffective amount of a therapeutic compound to a subject, such that thetherapeutic compound penetrates into the CNS and modulates the CNStarget to treat the CNS disorder. Accordingly, the therapeutic compoundcan have the formula:[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

In a more specific aspect of the invention, the invention is directed toa method of treating a sleep disorder. The method comprisesadministering an effective amount of a therapeutic compound to asubject, such that the sleep disorder is treated. Accordingly, thetherapeutic compound can have the formula:[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

In an additional aspect, the invention is directed to a method oftreating a sleep disorder target. The method comprises administering aneffective amount of a therapeutic compound to a subject, such that thesleep disorder is treated. Accordingly, the therapeutic compound canhave the formula:[AD]−(SP)_(n) −[EG]wherein AD is a moiety that agonizes an adenosine receptor or acollection of adenosine receptors, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

Another aspect of the invention is directed to a method of treating asleep disorder target. The method comprises administering an effectiveamount of a therapeutic compound to a subject, such that the sleepdisorder is treated. Accordingly, the therapeutic compound can have theformula:[AH]−(SP)_(n) −[DA]wherein AH is a moiety that antagonizes a histamine receptor or acollection of histamine receptors, DA is a drug activity modulatingmoiety that provides the ability to modulate the activity of thetherapeutic compound, SP is a spacer molecule, and n is 0 or 1.

In another aspect, the invention is directed to a method of treating asleep disorder. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disorder istreated. Accordingly, the therapeutic compound can have the formula:[AH]−(SP)_(n) −[EG]wherein AH is a moiety that antagonizes a histamine receptor or acollection of histamine receptors, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

Another aspect of the invention is a method of modulating a sleepdisorder target. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disordertarget is modulated, wherein the therapeutic compound comprises theformula:[CA]−(SP)_(n) −[DA]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, DA is a drug activitymodulating moiety that provides the ability to modulate the activity ofthe therapeutic compound, e.g., ester or carboxylic acid, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a method of modulating a sleepdisorder target. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disordertarget is modulated, wherein the therapeutic compound comprises theformula:[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a method of modulating a sleepdisorder target. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disordertarget is modulated, wherein the therapeutic compound comprises theformula:[AD]−(SP)_(n) −[EG]wherein AD is a moiety that agonizes an adenosine receptor or acollection of adenosine receptors, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

Another aspect of the invention is a method of modulating a sleepdisorder target. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disordertarget is modulated, wherein the therapeutic compound comprises theformula:[AH]−(SP)_(n) −[DA]wherein AH is a moiety that antagonizes a histamine receptor or acollection of histamine receptors, DA is a drug activity modulatingmoiety that provides the ability to modulate the activity of thetherapeutic compound, e.g., ester or carboxylic acid, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a method of modulating a sleepdisorder target. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disordertarget is modulated, wherein the therapeutic compound comprises theformula:[AH]−(SP)_(n) −[EG]wherein AH is a moiety that antagonizes a histamine receptor or acollection of histamine receptors, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

One aspect of the invention is a Central Nervous System (CNS) disordertarget modulator comprising the formula:[CA]−(SP)_(n) −[DA]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, DA is a drug activitymodulating moiety that provides the ability to modulate the activity ofthe therapeutic compound, e.g., ester or carboxylic acid, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a CNS disorder target modulatorcomprising the formula:[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a sleep disorder target modulatorcomprising the formula:[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

In a another aspect of the invention a sleep disorder target modulatorcomprises the formula:[AH]−(SP)_(n) −[DA]wherein AH is a moiety that antagonizes a histamine receptor, DA is adrug activity modulating moiety that provides the ability to modulatethe activity of the therapeutic compound, e.g., ester or carboxylicacid, SP is a spacer molecule, and n is 0 or 1.

In a particular aspect of the invention a sleep disorder targetmodulator comprises the formula:[AH]−(SP)_(n) −[EG]wherein AH is a moiety that antagonizes a histamine receptor, EG is anester group that modifies the half-life of the therapeutic compound, SPis a spacer molecule, and n is 0 or 1.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutic compound as prepared according to themethodology of this invention, and a pharmaceutically acceptablecarrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C are graphs depicting the effect of a compound of theinvention on parameters pertinent to sleep disorders.

FIGS. 2A-G are graphs depicting the binding of reference compounds tothe receptors as indicated.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to compositions used for treating CentralNervous System (CNS) disorders. In addition, the invention providesconvenient methods of treatment of a CNS disorder. Furthermore, theinvention provides methods of treating sleep disorders usingcompositions that remain active for a discrete period of time to reduceside effects. More specifically, the invention is directed to thecompositions and use of derivatized, e.g., ester or carboxylic acidderivatized, antihistamine antagonists for the treatment of sleepdisorders.

METHODS OF THE INVENTION

One embodiment of the invention is a method of treating a CentralNervous System (CNS) disorder. The method of treating comprises thetreatment of a Central Nervous System (CNS) disorder, comprisingadministering to a subject an effective amount of a therapeuticcompound, such that the therapeutic compound penetrates into the CNS andmodulates the CNS target, thereby treating the CNS disorder.

The language “Central Nervous System (CNS) disorder,” includes disordersor states of the central nervous system and that are treatable by thecompounds described herein. Examples include, but are not limited todepression; anxiety; addictions; obsessive compulsive disorder;affective neurosis/disorder; depressive neurosis/disorder; anxietyneurosis; dysthymic disorder; behavior disorder; mood disorder; sexualdysfunction; psychosexual dysfunction; sex disorder; sexual disorder;schizophrenia; manic depression; delirium; dementia; severe mentalretardation and dyskinesias such as Huntington' disease and Gilles de laTourett's syndrome; disturbed biological and circadian rhythms; feedingdisorders, such as anorexia, bulimia, cachexia, and obesity; diabetes;appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson'sdisease; Cushing's syndrome/disease; basophil adenoma; prolactinoma;hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma;hypothalamic diseases; Froehlich's syndrome; adrenohypophysis disease;hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kalirnan's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthhormone deficiency; dwarfism; gigantism; acromegaly; disturbedbiological and circadian rhythms; and sleep disturbances associated withsuch diseases as neurological disorders, neuropathic pain and restlessleg syndrome, heart and lung diseases; acute and congestive heartfailure; hypotension; hypertension; urinary retention; osteoporosis;angina pectoris; myocardial infarction; ischaemic or haemorrhagicstroke; subarachnoid haemorrhage; head injury such as subarachnoidhaemorrhage associated with traumatic head injury; ulcers; allergies;benign prostatic hypertrophy; chronic renal failure; renal disease;impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced orexaggerated sensitivity to pain, such as hyperalgesia, causalgia andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndromes I and II; arthriticpain; sports injury pain; pain related to infection, e.g., HIV,post-polio syndrome, and post-herpetic neuralgia; phantom limb pain;labor pain; cancer pain; post-chemotherapy pain; post-stroke pain;post-operative pain; neuralgia; conditions associated with visceral painincluding irritable bowel syndrome, migraine and angina; urinary bladderincontinence e.g. urge incontinence; tolerance to narcotics orwithdrawal from narcotics; sleep disorders, sleep apnea; narcolepsy,insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders,which include nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration, epilepsy and seizure disorders,attention-deficit hyperactivity disorder (ADHD)/cognition, Alzheimer's,drug abuse, stroke, multiple sclerosis (MS), and Amyotrophic LateralSclerosis (ALS).

The terms “treating” or “treatment” include administering atherapeutically effective amount of a compound sufficient to reduce oreliminate at least one symptom of the state, disease or disorder, e.g.,a sleep disorder.

The language “administering” includes delivery to a subject by any meansthat does not affect the ability of the therapeutic compound to performits intended function. The therapeutic compound may be administered byany means that sufficiently treats the disorder target. Administrationincludes, but is not limited to parenteral, enteral, and topicaladministration. While it is possible for a compound of the presentinvention to be administered alone, it is preferable to administer thecompound as a pharmaceutical composition, which includes compositionsthat comprise the compounds of the present invention and apharmaceutically acceptable carrier. In a specific embodiment, thetherapeutic compound is administered orally.

Administration also includes the use of an additional modulating factor(AMF) in “combination therapy.” The language “additional modulatingfactor (AMF)” includes additional factors, such as additionaltherapeutics or subject abnormalities, e.g., a chemical imbalance. Itshould be understood that the additional modulating factor may bedirected to the same or a different disorder target as that beingmodulated by the compounds of the present invention. The language“combination therapy” includes the co-administration of the modulatingcompound of the present invention in the presence of an additionalmodulating factor, e.g., an additional therapeutic agent. Administrationof the modulating compound may be first, followed by the othertherapeutic agent; or administration of the other therapeutic agent maybe first, followed by the modulating, e.g., inhibiting, compound. Theother therapeutic agent may be any agent which is known in the art totreat, prevent, or reduce the symptoms of the targeted disorder, e.g., asleep disorder. In addition, the compounds of the present invention canalso be administered in combination with other known therapies for thetarget disorder. Furthermore, the other therapeutic agent may be anyagent of benefit to the patient when administered in combination withthe administration of a modulating, e.g., inhibiting, compound. Theother therapeutic agent may also be a modulating compound. For example,a therapeutic compound of the invention may be administered inconjunction with a variety of commercially-available drugs, including,but not limited to, antimicrobial agents, such as pentamidine,lomefloxacin, metronidazole, fungistatic agents, germicidal agents,hormones, antipyretic agents, antidiabetic agents, bronchodilators, suchas aminophylline, antidiarrheal agents, such as diphenoxylatehydrochloride with atropine sulfate, antiarrhythmic agents, such asdisopyramide phosphate and bidisomide, coronary dilation agents,glycosides, spasmolytics, antihypertensive agents, such as verapamil andverapamil hydrochloride and their enantiomers, and betaxolol,antidepressants, antianxiety agents, other psychotherapeutic agents,such as zolpidem, cycloserine and milacemide, corticosteroids,analgesics, such as misoprostol with diclofenac, contraceptives, such asethynodiol diacetate with ethinyl estradiol, and norethynodrel withmestranol, nonsteroidal anti-inflammatory drugs, such as oxaprozen,blood glucose lowering agents, cholesterol lowering agents,anticonvulsant agents, other antiepileptic agents, inumunomodulators,antioholinergics, sympatholytics, sympathomimetics, vasodilatory agents,anticoagulants, antiarrhythmics, such as disopyramide or disobutamide,prostaglandins having various pharmacologic activities, such asmisoprostol and enisoprost, diuretics, such as spironolactone andspironolactone with hydrochlorothiazide, sleep aids, such as zolpidemtartrate, antihistaminic agents, antineoplastic agents, oncolyticagents, antiandrogens, antimalarial agents, antileprosy agents, andvarious other types of drugs. See Goodman and Gilman's The Basis ofTherapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990) and TheMerck Index (Eleventh Edition, Merck & Co., Inc., USA, 1989), each ofwhich is incorporated herein by reference

In addition, a compound of the invention also may be administered inconjunction with any one or combination of the commercially-available,over-the-counter or prescription medications, including, but not limitedto Avobenzene/padimate-O, ACCUPRIL® tablets (quinapril hydrochloride),Accutane capsules (isotretinoin), Achromycin V capsules (themonohydrochloride of (4S-(4.alpha., 4a.alpha.,5a.alpha.,6.beta.,12a.alpha.))-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,6,10,12,12a-pentBPydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide),Actifed cough syrup (codeine phosphate, triprolidine hydrochloride andpseudoephedrine hydrochloride), Aldactazide tablets (spironolactone andhydrochlorothiazide), ALDOCLOR® tablets (methyldopa and chlorothiazide),Aldoril tablets (methyldopa-hydrochlorothiazide), Alferon® N injection(interferon .alpha.-n3 (human leukocyte derived)), ALTACE™ capsules(ramipril), AMBIEN® tablets (zolpidem tartrate), Anafranil capsules(clomipramine hydrochloride), ANAPROX® tablets (naproxen sodium),Ancobon capsules (flucytosine), Ansaid tablets (flurbiprofen),Apresazide capsules (hydralazine hydrochloride and hydrochlorothiazide),Asendin tablets (2-chloro-11-(1-piperazinyl)dibenz(b,f)(1,4)-oxazepine),Atretol™ tablets (carbamazepine), Aureomycin ophthalmic ointment(chlortetracycline hydrochloride), Azo Gantanol® tablets(sulfamethoxazole and phenazopyridine hydrochloride), Azo Gantrisintablets (sulfisoxazole and phenazopyridine hydrochloride), Azulfidine®Dtablets and EN-tabs (5-((p-(2-pyridylsulfamoyl)phenyl)-azo)salicylicacid), Bactrim tablets (trimethoprim and sulfamethoxazole), Bactrim I.V.infusion (trimethoprim and sulfamethoxazole), Bactrim pediatricsuspension (trimethoprim and sulfamethoxazole), Bactrim suspension(trimethoprim and sulfamethoxazole), Bactrim tablets (trimethoprim andsulfamethoxazole), Benadryl®D capsules (diphenhydramine hydrochlorideUSP), Benadryl® kapseals (diphenhydramine hydrochloride USP),Benadryl®tablets (diphenhydramine hydrochloride USP), Benadryl®parenteral (diphenhydramine hydrochloride USP), Benadryl® steri-vials,ampoules, and steri-dose syringe (diphenhydramine hydrochloride USP),Capoten tablets (captopril), Capozide tablets(captopril-hydrochlorothiazide), Cardizem® CD capsules (diltiazemhydrochloride), Cardizem® SR capsules (diltiazem hydrochloride),Cardizem® tablets (diltiazem hydrochloride), Chibroxin sterileophthahnic solution (with oral form) (norfloxacin), Children's Advil®suspension (ibuprofen), Cipro® I.V. (ciprofloxacin), Cipro® tablets(ciprofloxacin), Claritin tablets (loratadine), Clinoril tablets(sulindac), Combipres® tablets (clonidine hydrochloride andchlorthalidone), Compazine® injection (prochlorperazine maleate),Compazine® multi-dose vials (prochlorperazine maleate), Compazine®syringes (prochlorperazine maleate), Compazine® spansule capsules(prochlorperazine maleate), Compazine® suppositories (prochlorperazinemaleate), Compazine® syrup (prochlorperazine maleate), Compazine®tablets (prochlorperazine maleate), Cordarone tablets (amiodaronehydrochloride), Corzide tablets (nadolol and bendroflumnethiazide),Dantrium capsules (dantrolene sodium), Dapsone tablets (4-4′diaminodiphenylsulfone), DAYPRO® caplets (oxaproxin), Declomycin tablets(demeclacycline or(4S-(4.alpha.,4a.alpha.,5a.alpha.,6.beta.,12a.alpha.))-7-Chloro-4-dimethylamino)-1,4,4a,5,5a,6, 11,12a-octBPydro-3,6,10,12,12a-pentBPydroxy-1,11-dioxo -2-naphthacenecarboxamide monohydrochloride), DECONAMINE®capsules (chlorpheniramine maleate and d-psuedoephedrine hydrochloride),DECONAMINE® syrup (chlorpheniramine maleate and d-psudoephedrinehydrochloride), DECONAMINE® tablets (chlorpheniramine maleate andd-psudoephedrine hydrochloride), Depakene capsules (valproic acid),Depakene syrup (valproic acid), Depakote sprinkle capsules (divalproexsodium), Depakote tablets (divalproex sodium), DiaBeta® tablets(glyburide), Diabinese tablets (chlorpropamide), Diamox parenteral(acetazolaamide), Diamox sequels (acetazolamide), Diamox tablets(acetazolamide), Dimetane-DC cough syrup (brompheniramine maleate,phenylpropanolamine hydrochloride and codeine phosphate), Dimetane-DXcough syrup (brompheniramine maleate, phenylpropanolamine hydrochlorideand codeine phosphate), Dipentum® capsules (olsalazine sodium),Diucardin tablets (hydroflumethiazide), Diupres tablets (reserpine andchlorothiazide), Diuril oral suspension (chlorothiazide), Diuril sodiumintravenous (chlorothiazide), Diuril tablets (chlorothiazide), Dolobidtablets (diflunisal), DORYXI capsules (doxycycline hyclate), Dyazidecapsules (hydrochlorothiazide and triamterene), Dyrenium capsules(triamterene), Efudex cream (5-fluorouracil), Efudex solutions(5-fluorouracil), Elavil injection (amitriptyline HCl), Elavil tablets(amitriptyline HCl), Eldepryl tablets (selegiline hydrochloride), Endeptablets (amitriptyline HCl), Enduron tablets (methyclothiazide),Enduronyl Forte tablets (methyclothiazide and deserpidine), Enduronyltablets (methyclothiazide and deserpidine), Ergamisol tablets(levamisole hydrochloride), Esidrix tablets (hydrochlorothiazide USP),Esimil tablets (guanethidine monosulfate USP and hydrochlorothiazideUSP), Etrafon Forte tablets (perphenazine, USP and amitriptylinehydrochloride, USP), Etrafon 2-10 tablets (perphenazine, USP andamitriptyline hydrochloride, USP), Etrafon tablets (perphenazine, USPand amitriptyline hydrochloride, USP), Etrafon-A tablets (perphenazine,USP and amnitriptyline hydrochloride, USP), Eulexin capsules(flutamide), Exna tablets (benzthiazide), FUDR injection (floxuridine),Fansidar tablets (N1-(5,6-dimethoxy-4-pyrimidinyl) sulfanilamide(sulfadoxine) and 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine(pyrimethamine), Feldene capsules (piroxicam), Flexeril tablets(cyclobenzaprine hydrochloride), FLOXIN® I.V. (ofloxacin injection),FLOXINS® tablets (ofloxacin), Fluorouracil injection (5-fluoro-2,4(1H,3H)-pyrimidinedione), Fulvicin tablets (griseofulvin), Gantanol®suspension (sulfamethoxazole), Gantanol® tablets (sulfamethoxazole),Gantrisin ophthalmic ointment/solution (sulfisoxazole), Gantrisinpediatric suspension (sulfisoxazole), Gantrisin syrup (sulfisoxazole),Gantrisin tablets (sulfisoxazole), Glucotrol tablets (glipizide),Glynase PresTab tablets (glyburide), Grifulvin V tablets(griseofuilvin), Grifulvin oral suspension (griseofuilvin), Gristactincapsules (griseofulvin), Grisactin tablets (griseofulvin), Gris-PEGtablets (griseofulvin), Grivate tablets (griseofuilvin), Grivatesuspension (griseofulvin), Haldol Decanoate 50 injection (haloperidoldecanoate), Haldol Decanoate 100 injection (haloperidol decanoate),Haldol tablets (haloperidol decanoate), Hibistat germicidal hand rinse(chlorhexidine gluconate), HISMANAL® tablets (astemizole), HydroDIURILtablets (hydrochlorothiazide), Hydromox tablets (quinethazone),Hydropres tablets (reserpine and hydrochlorothiazide), Inderide® tablets(propranolol hydrochloride and hydrochlorothiazide), Inderides capsule®(propranolol hydrochloride and hydrochlorothiazide), Intal inhaler(cromolyn sodium), Intron A injection (recombinantinterferon.alpha.-2b), Lamprene capsules (clofazimine), Lasix oralsolution (furosemide), Lasix tablets (furosemide), Lasix injection(furosernide), Limbitrol tablets (chlordiazepoxide and amitriptylinehydrochloride), Lodine capsules (etodolac), Lopressor HCT tablets(metoprolol tartrate USP and hydrochlorothiazide USP), Lotensin tablets(benazepril hydrochloride), LOZOLS tablets (indapamide), Ludiorniltablets (maprotiline hydrochloride USP), Marplan tablets(isocarboxazid), MAQUIN® tablets (lomefloxacin HCl), Maxzide tablets(triamterene USP and hydrochlorothiazide USP), Mellaril® concentrate(thioridazine), Mellaril® tablets (thioridazine), Mellaril-S suspension(thioridazine), Mepergan injection (meperidine hydrochloride andpromethazine hydrochloride), Methotrexate tablets (methotrexate),Mevacor tablets (lovastatin), Micronase tablets (glyburide), Minizidecapsules (prazosin hydrochloride and polythiazide), Minocin intravenous((4S-(4.alpha.,4a.alpha.,5a.alpha.,12a.alpha.))-4,7-bis(dimethylanlino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochforide), Minocin oral suspension((4S-(4.alpha.,4a.alpha.,5a.alpha.,12a.alpha.))-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrochloride), Minocin capsules((4S-(4.alpha.,4a.alpha.,5a.alpha.,12a.alpha.))-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride), Moduretic tablets (amilorideHCl-hydrochlorothiazide), Monodox®P capsules (doxycycline monohydrate),Monopril tablets (fosinopril sodium), Children's Motrin liquidsuspension (ibuprofen), Motrin tablets (ibuprofen), Mykrox tablets(metolazone), NAPROSYN® suspension (naproxen), NAPROSYN® tablets(naproxen), Navane capsules (thiothixene), Navane intramuscular(thiothixene), NegGram caplets (nalidixic acid), NegGram suspension(nalidixic acid), Neptazane tablets (methazolamide), Nipent injection(pentostatin), Normodyne tablets (labetalol HCl), NOROXIN tablets(norfloxacin), Norpramin tablets (desipramine hydrochloride USP), oretictablets (hydrochlorothiazide), Oreticyl Forte tablets(hydrochlorothiazide and deserpidine), Orinase tablets (tolbutamide),Omade capsules (phenylpropanolamine hydrochloride and chlorpheniraminemaleate), Orudis capsules (ketoprofen), Oxsoralen lotion(methoxypsoralen), PBZ tablets (tripelennamine hydrochloride USP),PBZ-SR tablets (tripelennamine hydrochloride USP), pHisoHex topicalemulsion (hexachlorophene), P & S PLUS® topical tar gel (crude coaltar), Pamelor® capsules (nortriptyline HCl), Pamelor® solution(nortriptyline HCl), Paxil tablets (paroxetine hydrochloride), Pediazoleoral suspension (erythromycin ethylsuccinate, USP and sulfisoxazoleacetyl, USP), Penetrex.TM. tablets (enoxacin), Pentasa capsules(mesalamine), Periactin syrup (cyproheptadine HCl), Periactin tablets(cyproheptadine HCl), Phenergan tablets (promethazine hydrochloride),Phenergan injection (promethazine hydrochloride), Phenergansuppositories (promethazine hydrochloride), Phenergan syrup(promethazine hydrochloride), Polytrim® ophthalmic solution(trimethoprim sulfate and polymyxin B sulfate), Pravachol (pravastatinsodium), Prinivil® tablets (lisinopril, MSD), Prinzide tablets(lisinopril-hydrochlorothiazide), Prolixin elixir (fluphenazinehydrochloride), Prolixin enanthate (fluphenazine hydrochloride),Prolixin injection (fluphenazine hydrochloride), Prolixin oralconcentrate (fluphenazine hydrochloride), Prolixin tablets (fluphenazinehydrochloride), ProSom tablets (estazolam), Prozac®D oral solution(fluoxetine hydrochloride), Prozac® oral Pulvules® (fluoxetinehydrochloride), Pyrazinamide tablets (pyrazinamide), QUINAGLUTE® tablets(quinidine gluconate), Quinidex tablets (quinidine sulfate), Relafentablets (nabumetone), Ru-Tuss II capsules (chlorpheniramine maleate andphenylpropanolamine hydrochloride), Seldane tablets (terfenadine),Septra tablets (trimethoprim and sulfamethoxazole), Septra suspension(trimethoprim and sulfamethoxazole), Septra I.V. infusion (trimethoprimand sulfamethoxazole), Septra tablets (trimethoprim andsulfamethoxazole), Ser-Ap-Es tablets (reserpine USP, hydralazinehydrochloride USP and hydrochlorothiazide USP), Sinequan capsules(doxepin HCl), Solganal injection (aurothioglucose, USP), Stelazineconcentrate (trifluoperazine hydrochloride), Stelazine injection(trifluoperazine hydrochloride), Stelazine tablets (trifluoperazinehydrochloride), Surmontil capsules (trimipramine maleate), SYMMETRELcapsules and syrup (amantadine hydrochloride), Taractan concentrate(chlorprothixene), Taractan injectable (chlorprothixene), Taractantablets (chlorprothixene), TAVIST® syrup (clemastine fumarate, USP),TAVIST® tablets (clemastine fumarate, USP), TAVIST®-1 12 hour reliefmedicine (clemastine fumarate, USP), TAVIST®-D 12 hour relief medicine(clemastine fumarate, USP), Tegretol Tablets (carbamazepine USP),Tegretol suspension (carbamazepine USP), Temaril tablets (trimeprazinetartrate), Temaril syrup (trimeprazine tartrate), Temaril capsules(trimeprazine tartrate), TENORETIC® tablets (atenolol andchlorthalidone), Terramycin intramuscular solution (oxytetracycline),Thiosulfil Forte tablets (sulfamethizole), Thorazine ampuls(chlorpromazine hydrochloride), Thorazine concentrate (chlorpromazinehydrochloride), Thorazine multi-dose vials (chlorpromazinehydrochloride), Thorazine capsules (chlorpromazine hydrochloride),Thorazine suppositories (chlorpromazine hydrochloride), Thorazine syrup(chlorpromazine hydrochloride), Thorazine tablets (chlorpromazinehydrochloride), Timolide tablets (timolol maleate-hydrochlorothiazide),Tofranil ampuls (imipramine hydrochloride USP), Tofranil tablets(imipramine hydrochloride USP), Tofranil capsules (imipraminehydrochloride USP), Tolinase tablets (tolazamide), Triaminic ExpectorantDH (Phenylpropanolamine hydrochloride and guaifenesin), Triaminic oralinfant drops (phenylpropanolamine hydrochloride, pheniramine maleate andpyrilamine maleate), Triavil tablets (perphenazine-amnitriptyline HCl),Trilafon concentrate (perphenazine USP), Trilafon injection(perphenazine USP), Trilafon tablets (perphenazine, USP), Trinalintablets (azatadine maleate, USP, and pseudoephedrine sulfate, USP),Vaseretic tablets (enalapril maleate-hydrochlorothiazide), Vasosulfopthalirc solution (sulfacetamide sodium-phenylephrine hydrochloride),Vasotec I.V. (enalapril maleate), Vasotec tablets (enalapril maleate),Velban® vials (vinblastine sulfate, USP), Vibramycin capsules(doxycycline monohydrate), Vibramycin intravenous (doxycyclinemonohydrate), Vibramycin oral suspension (doxycycline monohydrate),Vibra-Tabs tablets (oxytetracycline), Vivactil tablets (protriptylineHCl), Voltaren tablets (diclofenac sodium), X-SEB T® shampoo (crude coaltar), Zaroxolyn tablets (metolazone), ZESTORETIC® oral (lisinopril andhydrochlorothiazide), ZESTRIL® tablets (lisinopril), ZITHROMAX™capsules(azithromycin), Zocor tablets (simvastatin), ZOLOFT® tablets (sertralinehydrochloride) and others.

A compound of the invention may also be administered in conjunction withthe use of physical methods such as with light therapy or electricalstimulation.

The term “pharmaceutically acceptable carrier” include apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a compound(s) of thepresent invention within or to the subject such that it can perform itsintended function. Typically, such compounds are carried or transportedfrom one organ, or portion of the body, to another organ, or portion ofthe body. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;phosphate buffer solutions; and other non-toxic compatible substancesemployed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willgenerally be that amount of the compound which produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacitying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof. Besides inert diluents, theoral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, coloring,perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred.

The terms “parenteral administration” and “administered parenterally” asused herein means modes of administration other than enteral and topicaladministration, usually by injection, and includes, without limitation,intravenous, intramuscular, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

The terms “systemic administration,” “administered systematically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, for example,subcutaneous administration, such that it enters the patient's systemand thus, is possibly subject to metabolism and other like processes.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracistemally and topically, as by powders, ointments ordrops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the duration of the treatment, other drugs, compounds and/ormaterials used in combination with the particular compound employed, theage, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medicalarts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

The regimen of administration can affect what constitutes an effectiveamount. The disorder target modulators, e.g., CNS disorder targetmodulators, can be administered to the subject either prior to or afterthe onset of a CNS disorder associated state. Further, several divideddosages, as well as staggered dosages, can be administered daily orsequentially, or the dose can be continuously infused, or can be a bolusinjection. Further, the dosages of the disorder target modulators, e.g.,CNS disorder target modulators, compound(s) can be proportionallyincreased or decreased as indicated by the exigencies of the therapeuticor prophylactic situation.

The language “subject” includes anirnals (e.g., mammals, e.g., cats,dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears,primates (e.g., chimpanzees, gorillas, and humans) which are capable ofsuffering from a CNS associated disorder, e.g., a sleep disorder.

The language “therapeutically effective amount” of the compound is thatamount necessary or sufficient to treat or prevent a state associatedwith a disorder, e.g., CNS disorder. The effective amount can varydepending on such factors as the size and weight of the subject, thetype of illness, or the particular compound. For example, the choice ofthe therapeutic compound can affect what constitutes an “effectiveamount”. One of ordinary skill in the art would be able to study theaforementioned factors and make the determination regarding theeffective amount of the therapeutic compound without undueexperimentation.

The language “penetrates into the CNS” includes the favorable biologicalproperty of a compound of the current invention to pass though, orpenetrate, the blood brain barrier (EBB) and enter into the CNS.

The language “therapeutic compound” includes compounds of the inventioncapable of performing their intended function, e.g., treating CNSdisorders and/or modulating CNS targets. The therapeutic compounds ofthe invention are described in detail herein.

Accordingly, the therapeutic compound can have the formula:[CA]−(SP)_(n) −[DA]wherein CA includes moieties that modulate an active CNS target receptoror a collection of active CNS target receptors.

The language “drug activity modulating moiety”, or “DA” is a moiety thatprovides the ability to modulate the activity of the therapeuticcompound. Examples include functional moieties, e.g., ester, carboxylicacid or alcohol groups, selected and positioned within the therapeuticdrug to provide the ability to modulate the activity of the drug, e.g.,modulate, e.g., increase, the half-life of the drug, the ability of thedrug to cross the blood brain barrier, or the ability of the drug tobind selectively to the desired receptor. In certain embodiments of theinvention, the drug activity modulating moiety is an ester group, EG. Inparticular embodiments, the activity of the drug, e.g., half-life, ofthe therapeutic drug is modulated by controlling the rate of hydrolysisof the ester group by selection and positioning of steric bulk near theester carbonyl of the ester group. In certain embodiments, the stericbulk is provided by the selection of a bulky ester group. In alternativeembodiments the steric bulk is provided by substitution selected andpositioned on the CA moiety, e.g., an AH moiety, near the carbonyl ofthe ester group.

In a specific embodiment, the drug activity modulating moiety is acarboxylic acid. In certain embodiments of the invention, the presenceof the carboxylic acid results in increased concentration of thetherapeutic compound within the CNS for a discrete period of time as aresult of the existence of an ionic bond that includes the carboxylateion of the corresponding carboxylic acid, e.g., zwitterion speciesformation with a nitrogen atom within the compound or salt bridgeformation. In one embodiment, penetration through the blood brainbarrier into the CNS results from the lipophilicity of substituents orconformational lipophilicity, i.e., lipophilicity as a result of aparticular conformation, such as internal salt formation between acarboxylate anion and a protonated amine. In another embodiment, thepresence of the carboxylic acid improves the ability of the compound tobind selectively to the desired receptor.

The language “ester group” includes an organic ester functionality thatis selected and positioned within the compound providing the ability tomodulate the activity or modify the properties of the correspondingtherapeutic compound. The organic ester group may be terminal, e.g., asubstituent, or internal. The carboxylate of the ester may be orientedfrom left to right or from right to left, e.g., a reverse ester.Examples of esters of the current invention include, but are not limitedto hydrocarbons and perfluorocarbons. In a preferred embodiment, thehydrocarbons posses 1 to 20 carbons. In certain embodiments, thehydrocarbons can be linear, branched, cyclic, aromatic, and acombination of aliphatic and aromatic, which are optionally substitutedwith O, N, S, and/or halogens and may additionally include a center ofchirality. In particular embodiments, the ester can be an n-propyl, anisopropyl, a t-butyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and abenzyl group.

The language “bulky ester” is intended to include an ester that hassufficient steric properties such that the rate of hydrolysis of thetherapeutic compound is modulated, e.g., reduced, such that the activityof the therapeutic compound is modified, e.g., the length of activity isincreased (i.e., the half-life of the therapeutic compound isincreased). Examples of bulky ester groups are depicted in Table 1.TABLE 1 Bulky Groups for H1 Antagonist Esters

Type A:

Type B:

In certain embodiments, the ester is not methyl, ethyl, or n-propyl. Incertain embodiments of the invention, the bulky ester is not ann-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl ester. In certainembodiments of the invention, the ester is not a C-1 to C-4 ester. Incertain embodiments of the invention wherein the therapeutic compound isa diphenhydramine-like, triprolidine-like, and doxepin-like compound,the ester is not a C-1 to C-4 ester and/or a C-3 to C-4 bulky ester.

The language “hydrocarbon” as used herein, includes substituted orunsubstituted alkyl, alkenyl, alkynyl, and aromatic or aryl moieties.The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.The term alkyl further includes alkyl groups, which can further includeoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morecarbons of the hydrocarbon backbone. In certain embodiments, a straightchain or branched chain alkyl has 6 or fewer carbon atoms in itsbackbone (e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain), andmore preferably 4 or fewer. Likewise, preferred cycloalkyls have from3-8 carbon atoms in their ring structure, and more preferably have 5 or6 carbons in the ring structure. The term C₁-C₆ includes alkyl groupscontaining 1 to 6 carbon atoms.

Moreover, the term alkyl includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamiino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). The term “alkyl” also includes the side chains of natural andunnatural amino acids.

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, benzene, phenyl, pyrrole, furan, thiophene, thiazole,isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole,isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and thelike. Furthermore, the term “aryl” includes multicyclic aryl groups,e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole,benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,benzofuran, purine, benzofuran, deazapurine, or indolizine. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles”, “heterocycles,” “heteroaryls” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings which are not aromatic so as to form apolycycle (e.g., tetralin).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, but thatcontain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl(alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenylgroups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. Theterm alkenyl further includes alkenyl groups which include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain orbranched chain alkenyl group has 6 or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from 3-8 carbon atoms in their ringstructure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups which include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulffhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto five carbon atoms in its backbone structure. “Lower alkenyl” and“lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.

The term “acyl” includes compounds and moieties that contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl “groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc.

The terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” includealkyl groups, as described above, which further include oxygen, nitrogenor sulfur atoms replacing one or more carbons of the hydrocarbonbackbone, e.g., oxygen, nitrogen or sulfur atoms.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups. Examples of substituted alkoxy groups includehalogenated alkoxy groups. The alkoxy groups can be substituted withgroups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulflhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties. Examples ofhalogen substituted alkoxy groups include, but are not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,dichloromethoxy, trichloromethoxy, etc.

The term “amine” or “amino” includes compounds where a nitrogen atom iscovalently bonded to at least one carbon or heteroatom. The term “alkylamino” includes groups and compounds wherein the nitrogen is bound to atleast one additional alkyl group. The term “dialkyl amino” includesgroups wherein the nitrogen atom is bound to at least two additionalalkyl groups. The term “arylamino” and “diarylamino” include groupswherein the nitrogen is bound to at least one or two aryl groups,respectively. The term “alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group that is bound to at least onealkyl group and at least one aryl group. The term “alkaminoalkyl” refersto an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom that isalso bound to an alkyl group.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl, or alkynyl groups bound to an amino group boundto a carboxy group. It includes arylaminocarboxy groups that includearyl or heteroaryl moieties bound to an amino group that is bound to thecarbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarboxy,” “alkenylaminocarboxy,” “a “kynylaminocarboxy,” and“arylaminocarboxy” include moieties wherein alkyl, alkenyl, aLkynyl andaryl moieties, respectively, are bound to a nitrogen atom which is inturn bound to the carbon of a carbonyl group.

The term “carbonyl” or “carboxy” includes compounds and moieties thatcontains a carbon connected with a double bond to an oxygen atom.Examples of moieties that contain a carbonyl include aldehydes, ketones,carboxylic acids, amides, esters, anhydrides, etc.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietiesthat contain a carbon connected with a double bond to a sulfur atom.

The term “ether” includes compounds or moieties that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group.

The term “thioether” includes compounds and moieties that contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkhioalkynyls. The term “alkioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom that is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkhioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomthat is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an H or O.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated,” e.g., perfluorinated, generally refers to amoiety, e.g., perfluorocarbons, wherein all hydrogens are replaced byhalogen atoms, e.g., fluorine.

The terms “polycyclyl” or “polycyclic radical” refer to two or morecyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

In certain embodiments, the ester group does not substantially effectthe biological activity of the therapeutic compound. Alternatively, incertain other embodiments the ester group significantly effects thebiological activity of the therapeutic compound. In one embodiment ofthe invention, the ester group improves the biological activity of thetherapeutic compound.

When the ester is a methyl or an ethyl ester, the formulation of thetherapeutic compound is formulated to sufficiently treat the targetdisorder. In addition, formulations of the therapeutic compound can beused to provide controlled in vivo adsorption of the therapeuticcompound over a discrete period of time.

In certain embodiments of the invention, the compound containing thedrug activity modulating group, e.g., an ester, carboxylic acid, oralcohol group, possesses an improved selectivity of the drug for adesired receptor versus an undesired receptors over the correspondingcompound without this group. In certain embodiments of the invention,the compound containing the drug activity modulating group, e.g., anester, carboxylic acid, or alcohol group, is more active as atherapeutic agent for treating disorders than the corresponding compoundwithout this group. In specific embodiments, the ester is more active asa therapeutic agent for treating disorders than the corresponding acidof the ester. In particular embodiments, the corresponding acid of theester is not a therapeutically active agent for treating disorders. Inalternative embodiments, the corresponding acid of an ester is moreactive as a therapeutic agent for treating disorders than thecorresponding ester of the acid. In a particular embodiment, thecarboxylic acid drug activity modulating group provides an internal saltwith an amine and facilitates crossing the blood brain barrier.

One skilled in the art would recognize that the ester groups, asdescribed above, could be extended to thioesters. Labile amides may alsobe used in replacement of the ester group, wherein the in vivohydrolysis would be performed by peptidases in the CNS.

The language “biological activity” includes activity associated with theintended biological function of the compounds of the present invention,e.g., treating a CNS disorder.

The language “modulate a target” or “modulation of a target” includesthe act of agonizing or antagonizing a receptor or group of receptors ofa target disorder. Thus, a compound that agonizes or antagonizes areceptor or group of receptors is referred to herein as a targetmodulator, e.g., CNS disorder target modulator. The language “targetmodulator” includes compounds or compositions, e.g., pharmaceuticalcompositions, which are used to modulate a target, e.g, a CNS disordertarget, e.g., a sleep disorder target

The terms “modification” or “modifies” include controlling or adjustingphysical or chemical parameters, e.g., the half-life, of the therapeuticcompound in vivo by changing one or more factors, e.g., thelipophilicity, electronic properties and/or steric size of the drugactivity modulating moiety, e.g., ester group.

The language “spacer molecule” or “SP” includes molecules or moietiesthat are positioned within the compound to allow the compound to performits intended function. In certain embodiments, the spacer molecule maybe present. Alternatively, in certain other embodiments, the spacermolecule may not be present. In certain embodiments, the spacer moleculemay be (CH₂)_(m), where m is an integer number selected from 1 to 20. Inaddition, the spacer molecule, e.g., the (CH₂)_(m) linker to an ester ora carboxylic acid group, can be substituted with one or moresubstituents. In one embodiment, the spacer molecule ismono-substituted. In another embodiment of the invention, the spacermolecule is disubstituted. In particular embodiments, the linkers of theinvention may be geminally-dialkylated, e.g., gem-dimethylated, singlysubstituted with a substituent other than a noncyclic alkyl group, e.g.,a heteroatom, or a cyclic substituent wherein one or more of the carbonsof the spacer molecule is contained in the ring, e.g., heterocycle(e.g., tetrahydropyran or tetrahydrofuran), or cyclic alkyl, e.g.,cyclopropyl. However, the substitution of the spacer molecule isindependent of the substitution elsewhere in the molecule.

The term “target” includes a receptor or group of receptors that havebeen identified as useful point of action for a therapeutic compound,e.g., CNS target, e.g., sleep disorder target, e.g., histamine receptor.

The language “receptor” includes specific sites of binding or actionwithin a subject, associated or responsible for the activity of thetarget disorder, e.g., a histamine or adenosine receptor.

The language “group of receptors” includes two or more receptors thatmay comprise the same receptor type or may comprise two or more receptortypes.

In particular, the therapeutic compound of the invention may comprisethe formula:[CA]−(SP)_(n) −[EG]wherein CA is a compound that modulates an active CNS target receptor ora collection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

In certain embodiments, the CNS disorder is a sleep disorder. Inparticular embodiments of the current invention wherein the CNS disorderis a sleep disorder, the therapeutic compound of the invention maycomprise one of the formulae:[AD]−(SP)_(n) −[EG][AH]−(SP)_(n) −[DA], or[AH]−(SP)_(n) −[EG]wherein AH is a compound that antagonizes a histamine receptor or acollection of histamine receptors, AD is a compound that agonizes anadenosine receptor or a collection of adenosine receptors, DA is a drugactivity modulating moiety that provides the ability to modulate theactivity of the therapeutic compound, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

The language “compounds that agonize” a receptor, e.g., agonizes anadenosine receptor, are intended to include compounds that induce theactivity of the receptor and agents that up-regulate (i.e., induce) thesynthesis or production of the receptor.

The language “compounds that antagonize” a receptor, e.g., a histaminereceptor, are intended to include compounds that inhibit the activity ofthe receptor and agents that down-regulate (i.e., inhibit) the synthesisor production of the receptor.

The language “adenosine receptor agonist” is intended to include artrecognized allosteric and nonallosteric adenosine receptor agonists,including, but not limited to cyclohexyladenosine, pentostatin,conformycin, and purine and adenyl derivatives that useful as adenosineprecursors for the enhancement of adenosine synthesis. Adenosine hasbeen reported to have cardioprotective and neuroprotective properties.It is reportedly released from cells in response to alterations in thesupply of or demand for oxygen, is said to be a potent vasodilator, andis believed to be involved in the metabolic regulation of blood flow.However, adenosine has a short half-life (<1 sec) in human blood, andtherefore high doses of adenosine would need to be administeredcontinuously to achieve effective levels. However, high doses ofadenosine have been reported to be toxic, and thus limit its therapeuticpotential. It is also believed that by increasing adenosineconcentration locally, i.e., at the target site within the targettissue, the beneficial effects of adenosine can be provided and thetoxic systemic effects minimized. In certain embodiments of theinvention, the therapeutic compounds of formula [AD]−(SP)_(n)−[EG],described above, may be used in the methods of the current invention toincrease the local adenosine concentration.

The language “histamine antagonist,” “antihistamine” and “[AH]” are usedinterchangeably and are intended to include any compound thatantagonizes a histamine or group of histamine receptors. In certainembodiments, the compound of the invention will bind to a histaminereceptor with an affinity of less than about 100 μM, e.g., less thanabout 10 μM. In one embodiment, antihistamines of the present inventioncontain at least two aryl rings that are separated by about 2-5 atomsfrom a basic nitrogen atom in specific embodiments, the two aryl ringsare connected to the same atom. The language “histamine antagonist” isintended to include art-recognized antihistamines, including both firstand second generation antihistamines. For example, the antihistamines ofthe invention include, but are not limited to, antihistamines such asethylenediamines, ethanolamines, alkylamines, phenothiazines,piperazines, piperdines, ketotifen, ebastine, terfenadine, acrivastine,triprolidine, doxepin, amitriptyline, triipramine, protriptyline,nortriptyline, desipramine, pheniramine, diphenhydramine, mequitazine,cyproheptadine, clemastine, diphenylpyraline, promethazine,homochlorocyclizine, alimemazine, mepyramine, methapyraline, peroxatine,trazodone, nefazodone, hydroxyzine, meclizine loratidine, azelastine,levocabastine, cetirizine, fexofenadine, mizolastine, mirtazapine, andastemizole.

Classes of antihistamines of the instant invention also includepheniramine-like compounds, doxepin-like compounds, diphenhydramine-likecompounds, triprolidine-like compounds, pheniramine analogs, andacrivastine analogs (see for example, Tables 2 and 3). It should beunderstood that the classes of antihistamines can be substituted orunsubstituted. In addition, the substituent(s) is selected andpositioned within the molecule such that the compound is able to performits intended function. Specific examples and locations of thesubstituents are discussed below.

The language “pheniramine-like compounds” is intended to includeantihistamines that include two aryl groups linked to the same atom, notlinked through a tricyclic ring system. In addition, pheniramine-likecompounds are distinguished from diphenhydramine-like compounds by thelack of an oxygen atom linking the carbon atom, which is attached to thearyl groups, to a piperidine ring. In certain embodiments, thepheniramine-like compounds are represented by Formula (I) and Formula(II):

wherein a 0 through 5, b 0 through 5, and R is H or any group whichimparts properties to the therapeutic compound to promote penetrationinto the CNS and to modify the half-life of the compound.

The language “diphenhydramine-like compounds” is intended to includeantihistamines that include two aryl groups linked to the same atom, notlinked through a tricyclic ring system, and are distinguished by thepresence of an oxygen atom linking the carbon atom, which is attached tothe aryl groups, to a piperidine ring. In certain embodiments, thediphenhydramine-like compounds are represented by Formula (III):

wherein c=0 through 5, and R is H or any group which imparts propertiesto the therapeutic compound to promote penetration into the CNS and tomodify the half-life of the compound.

The language “doxepin-like compounds” is intended to include analogs ofdoxepine or antihistamines that include two aryl groups linked to thesame atom that are linked through a tricyclic ring system, e.g. a sevenmembered ring (i.e., similar to that of doxepine). In addition,doxepin-like compounds may posses a piperidine ring or the ring can bereplaced by a linear structure, e.g., an alkylene group (i.e., similarto that of doxepine). In certain embodiments, the doxepin-like compoundsare represented by Formula (VI):

wherein the dashed line represents a single or double bond; R₁ and R₂are substituents that are selected such that the compound can performits intended function, e.g., substituents that are described forantihistamines; X₁ is O, S, H, or CH₂ and n 1 to 6. In one embodiment, nis 1 to 4. In a specific embodiment, n is 1, 2, or 3.

The language “triprolidine-like compounds” is intended to includeantihistamines that include two aryl groups linked to the same atom, notlinked through a tricyclic ring system, and are distinguished by thepresence of a pyrrolidine ring. In certain embodiments, thetriprolidine-like compounds are represented by Formula (IV):

wherein d 0 through 5, e=0 through 4, g=0 through 5, the dashed linerepresents a single or double bond, R and R₁ are independently H or anygroup which imparts properties to the therapeutic compound to promotepenetration into the CNS and to modify the half-life of the compound,and p and q are 0 or 1. In certain embodiments, p and q are not both 1.The (CH₂)_(m) linker to the ester or carboxylic acid group, can besubstituted with one or more substituents.

The language “acrivastine analogs” is intended to include the particularembodiment of Formula (IV), wherein the side chain that contains theCO₂R is an acrylate, e.g., acrylic acid (as depicted in Scheme 1).

The language “pheniramine analogs” is intended to include antihistaminesthat include two aryl groups linked to the same atom, not linked througha tricyclic ring system. In addition, pheniramine analogs aredistinguished by the presence of a dimethylamine moiety. In certainembodiments, the pheniramine analogs are represented by Formula (V):

wherein f 0 through 5, h=0 through 5, the dashed line represents asingle or double bond, R and R₁ are independently H or any group whichimparts properties to the therapeutic compound to promote penetrationinto the CNS and to modify the half-life of the compound, X₂ is CH or N,and r and t are 0 or 1. In certain embodiments, r and t are not both 1.The (CH₂)_(m) linker to the ester or carboxylic acid group, can besubstituted with one or more substituents.

An antihistamine of the instant invention may be substituted by one ormore substituents, which are selected and positioned within the moleculesuch that the compound is able to perform its intended function. Forexample, the substituent(s) can be located on any available position,such as, the aryl rings, the spacer molecule, the drug activitymodulating moiety, any branching moieties, or on other substituents.Exemplary substituents include substituted or unsubstituted alkyl,alkenyl, alkynyl, and aromatic or aryl moieties as defined herein. Inparticular, the antihistamines of the invention may be substituted bysubstituents including, but not limited to, hydrogen; halogen, e.g.bromide, chloride, or fluoride; dimethylaminocarbonyl; fluoroalkyl,e.g., trifluoromethyl; hydroxy; alkyl, e.g., C₁₋₆ alkyl, e.g., methyl orethyl; alkoxy, e.g., C₁₋₆ alkoxy, e.g., methoxy or propoxy; carboxylicacid; methylhydroxy; methylcarbonyl; cyano; aminomethyl; (aminoalkyl);ethoxycarbonylmethoxy; cyanomethyloxy; (acetoxyethyl)oxy;(hydroxyoxyethyl)oxy; morphilinoethyloxy; (tetrazol-5-yl)methyloxy;carboxymethyloxy; dimethylaminocarbonylmethyloxy;morphilinocarbonylmethyloxy; (1-ethoxycarbonyl-1-methylethyl)oxy;(1-carboxy-1 methylethyl)oxy;(2-methoxyethyl)oxy;(1-dimethylaminocarbonyl-1-methylethyl)oxy;(1-ethoxycarbonyl)cyclobutoxy; (1-carboxy)cyclobutoxy;(1;1-dimethyl-2-hydroxyethyl)oxy; (2;2-dimethyl-2-hydroxyethyl)oxy;acyloxy; cycloalkyl; arylalkyl; alkoxycarbonyl; and substituted orunsubstituted amines.

In certain embodiments, the aryl rings may be substituted with one ormore substituents, each of which may be different or the same, andinclude, for example, hydrogen, halogens, alkyl, fluoroalkyl, e.g.,trifluoromethyl, hydroxy, alkoxy, and other substituents, such as,—(O)_(u)—(CH₂)_(t)—C(O)OR₄, —(O)_(u)—(CH₂)_(t)—OC(O)R₄,—(O)_(u)—(CH₂)_(t)—C(O)—NR₅R₆ or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R₄ wherein:t is an integer, such as an integer from zero to about three, and themethylene group —(CH₂)_(t)— can be substituted or unsubstituted; and R₄,R₅ or R₆ are independently hydrogen, an aliphatic group, a substitutedaliphatic group, an aromatic group, a substituted aromatic group or anon-aromatic heterocyclic group. Alternatively, R₅ and R₆, takentogether with the nitrogen atom to which they are bonded, can form anon-aromatic heterocyclic ring.

Suitable substituents on an aliphatic group, aromatic group (carbocyclicand heteroaryl), non-aromatic heterocyclic ring or benzyl group include,for example, an electron withdrawing group, a halogen, azido, cyano,fluoroalkyl, e.g., trifluoromethyl, carboxylic acid, hydroxy, —CONR₈ R₉,—NR₈ R₉, —OS(O)₂ NR₈ R₉, —S(O)₂ NR₈ R₉, sulfonic acid, sulfonamide,guanidino, —(O)_(u)—(CH₂)_(t)—C(O)OR₄, —(O)_(u)—(CH₂)_(t)—OC (O) R₄,—(O)_(u)—(CH₂)_(t)—C(O)—NR₅ R₆, —(O)_(u)—(CH₂)_(t)—NHC(O)O—R₄, —Q—H,—Q-(aliphatic group), —Q-(substituted aliphatic group), —Q-(aryl),—Q-(aromatic group), —Q-(substituted aromatic group),—Q—(CH₂)_(p)-(substituted or unsubstituted aromatic group),—Q-(non-aromatic heterocyclic group) or —Q—(CH₂)_(p)-(non-aromaticheterocyclic group) wherein: p is an integer from 1-5; R₄, R₅ or R₆ areindependently —H, an aliphatic group, a substituted aliphatic group, anaromatic group, a substituted aromatic group, a non-aromaticheterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromaticgroup) or —NHC(O)—O-(non-aromatic heterocyclic group); R₅ and R₆, takentogether with the nitrogen atom to which they are bonded, can form anon-aromatic heterocyclic ring; t is an integer from zero to aboutthree; the methylene group, —(CH₂)_(t)—, can be substituted orunsubstituted; and Q is —O—, —S—, —S(O)—, —S(O)₂—, —OS(O)₂—, —C(O)—,—OC(O)—, —C(O)O—, —C(O)C(O)—O—, —O—C(O)C(O)—, —C(O)NH—, —NHC(O)—,—OC(O)NH—, —NHC(O)O—, —NH—C(O)—NH—, —S(O)₂ NH—, —NHS(O)₂—, —N(R₇)—,—C(NR₇)NHNH—, —NHC(NR₇)—, —NR₈C(O)— or —NR₈ S(O)₂— wherein: R₇ ishydrogen, an aliphatic group, a benzyl group, an aryl group ornon-aromatic heterocyclic group; R₈ and R₉ are independently hydrogen,hydroxy, an aliphatic group, a substituted aliphatic group, a benzylgroup, an aryl group or non-aromatic heterocyclic group; and u is zeroor one.

A substituted non-aromatic heterocyclic ring, benzyl group or aromaticgroup can also have an aliphatic or substituted aliphatic group, as asubstituent. In addition, a substituted aliphatic group can also have anoxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group,substituted benzyl group, aromatic group or substituted aromatic groupas a substituent. A substituted non-aromatic heterocyclic ring can alsohave ═O, ═S, ═NH or ═N(aliphatic, aromatic or substituted aromaticgroup) as a substituent. A substituted aliphatic, substituted aromatic,substituted non-aromatic heterocyclic ring or substituted benzyl groupcan have more than one substituent. Acyl groups include substituted andunsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyland aromatic sulfonyl. Suitable electron withdrawing groups include, forexample, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkylesters, —CH═NH, —CN, —NO₂ and halogens.

In certain embodiments of the invention, the therapeutic compound has afavorable biological property. In one embodiment of the invention, theinvention is a method of treating a sleep disorder. The method comprisesadministering an effective amount of an antihistamine compound, suchthat the sleep disorder is treated, wherein the antihistamine compoundhas a favorable biological property (FBP).

The language “favorable biological property (FBP)” includes one or morebiological properties that allow the compound to perform its intendedfunction in an enhanced manner. Examples of favorable biologicalproperties include but are not limited to induction of a discrete sleepor hypnotic state, activity of the therapeutic compound for a discreteperiod of time, penetration through the blood brain barrier into theCNS, e.g., resulting from lipophilicity of substituents orconformational lipophilicity (i.e., lipophilicity as a result of aparticular conformation, such as internal salt formation between acarboxylate anion and a protonated amine), modulation of the half-lifeof the therapeutic compound, in vivo hydrolysis of an ester by esterasesthat allows sequestration of the therapeutic compound in the CNS, analteration of charge, an alteration of pharmacology-kinetics, analteration of log P by a value of 1 or more, increased receptorselectivity, reduced peripheral half-life, the ability to increasedosage, increased peripheral elimination, decreased anti-muscarinicactivity, decreased anti-cholinergic, and any combination thereof. Itshould be understood that the language “FPB” is intended to include asingle property or a combination of two or more properties. Inparticular embodiments of the invention, the therapeutic compoundinduces a discrete sleep or hypnotic state by penetration into the CNS.In certain embodiments of the invention, the FBP includes increasedconcentration within the CNS for a discrete period of time as a resultof a slower rate of conversion to the corresponding carboxylic acid byin vivo esterase activity within the CNS as compared with the periphery.In another embodiment of the invention, the FBP includes increasedconcentration within the CNS for a discrete period of time as a resultof the existence of an ionic bond that includes the carboxylate ion ofthe corresponding carboxylic acid, e.g., zwitterion species formationwith a nitrogen atom within the compound or salt bridge formation.

In certain embodiments, wherein the therapeutic compound is active for adiscrete period of time, the FBP is a reduced ability of the subject toform a tolerance to the therapeutic compound. The language “tolerance”includes the natural tendency of a subject to become less affected bycontinued administration of a particular therapeutic compound due torepeated exposure to the compound. It should be noted that tolerance istypically increased coincident with the increased time that a compoundis present in its active state within the subject. Reduced tolerancewould coincide with increased therapeutic effectiveness.

The language “discrete sleep or hypnotic state” include a state ofconsciousness that is induced by the presence of active therapeuticcompound of the invention, for a defined period of time. This is incontrast to the lingering hangover effect resulting from the existingtreatments, e.g., antihistamines, used for their sedative effect thatmaintain active drug concentrations for extended periods of time in theperiphery.

The language “discrete period of time” includes a defined period of timein which the therapeutic compound is active, and depends upon thephysical and reactive properties of the ester group. In one embodimentof the invention, the half-life of the therapeutic compound is 1 to 8hours. In a preferred embodiment, the half-life of the therapeuticcompound is 6 hours.

The language “sequestration” includes having enhanced concentration inthe CNS and more rapid elimination from the periphery. The product ofhydrolysis can exit the brain by various carboxylate excretionmechanisms, possibly at a slower rate than from the periphery producinga CNS sequestration of the carboxylate for a defined, or discrete,period of time. In one embodiment of the invention, elimination of thehydrolyzed carboxylate-containing metabolite occurs predominately byexcretion though the kidneys, due to enhanced polarity of themetabolite, either as the free carboxylate or after Phase II furthermetabolism. In another embodiment, elimination occurs predominately bymetabolism in the liver, e.g. hydrolysis of the ester followed byglucuronidation, and excretion into the bile. In certain embodiments,the brain assists in the elimination.

Another embodiment of the current invention is a method of modulating asleep disorder target comprising administering to a subject an effectiveamount of a therapeutic compound, such that the therapeutic compoundpenetrates into the CNS and modulates the sleep disorder target, whereinthe therapeutic compound is as described above and comprises any one ofthe following formulae:[CA]−(SP)_(n) −[DA],[CA]−(SP)_(n) −[EG],[AD]−(SP)_(n) −[EG],[AH]−(SP)_(n) −[DA], or[AH]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, AD is a moiety that agonizesan adenosine receptor or a collection of adenosine receptors, AH is amoiety that antagonizes a histamine receptor or a collection ofhistamine receptors, DA is a drug activity modulating moiety thatprovides the ability to modulate the activity of the therapeuticcompound, EG is an ester group that modifies the half-life of thetherapeutic compound, SP is a spacer molecule, and n is 0 or 1.

In an additional embodiment, the invention is a CNS disorder targetmodulator comprising the formula:[CA]−(SP)_(n) −[DA], or[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, DA is a drug activitymodulating moiety that provides the ability to modulate the activity ofthe therapeutic compound, EG is an ester group that modifies thehalf-life of the therapeutic compound, SP is a spacer molecule, and n is0 or 1.

Another embodiment of the invention is a sleep disorder target modulatorcomprising the formula:[CA]−(SP)_(n) −[EG]wherein CA is a moiety that modulates an active CNS target receptor or acollection of active CNS target receptors, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

In a particular embodiment of the invention, a sleep disorder targetmodulator comprises the formula:[AH]−(SP)_(n) −[DA] or[AH]−(SP)_(n) −[EG]wherein AH is a moiety that antagonizes a histamine receptor or acollection of histamine receptors, DA is a drug activity modulatingmoiety that provides the ability to modulate the activity of thetherapeutic compound, EG is an ester group that modifies the half-lifeof the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.

In accord with the invention, particular embodiments of thepheniramine-like therapeutic compound used for treating CNS disorders,e.g., sleep disorders, are:

wherein a=0 through 5, b=0 through 5, and R is H or any group whichimparts properties to the therapeutic compound to promote penetrationinto the CNS and to modify the half-life of the compound. In anotherembodiment of the therapeutic compound used for the treatment of adisorder, the diphenhydramine-like therapeutic compound is:

c=0 through 5, and R is H or any group which imparts properties to thetherapeutic compound to promote penetration into the CNS and to modifythe half-life of the compound.

In another embodiment of the therapeutic compound used for the treatmentof a disorder, the triprolidine-like therapeutic compound is:

wherein d=0 through 5, e=0 through 4, the dashed line represents asingle or double bond, and R is H or any group which imparts propertiesto the therapeutic compound to promote penetration into the CNS and tomodify the half-life of the compound.

In another embodiment of the therapeutic compound used for the treatmentof a disorder, the pheniramine analog therapeutic compound is:

wherein f=0 through 5, the dashed line represents a single or doublebond, and R is H or any group which imparts properties to thetherapeutic compound to promote penetration into the CNS and to modifythe half-life of the compound.

In preferred embodiments of the invention, a=0 or 1; b=0 or 1; c=0 or 1;d=1 or 2; e=1 or 2; and f=1 or 2. In particular embodiments of Formulae(1), (1) (III), (IV), and (VI), R is a bulky ester.

In one embodiment, the compound of the invention is doxepin,pheniramine, diphenhydramine, triprolidine, or acrivastine.

An additional embodiment of the invention is the composition of severalanalogs of doxepin and acrivastine. The structures of several compounds,as well as their activity, are shown in Scheme 1. These compounds havedemonstrated anti-H1 activity related to other antihistamine compoundsof the invention. SCHEME 1

References: ¹H. Muramatsu et al, Chem. Pharm. Bull. 41(11), 1987(1993),²N. Iwasaki et al, Chem. Pharm. Bull. 42(11), 2285(1994),³E. Ohshima, et al., J. Med. Chem. 35, 2074(1992).

In particular embodiments of the invention, the doxepin-like therapeuticcompound is represented by the following formula:

wherein

-   -   the dashed line represents a single or double bond;    -   R₁═H, OH, CH₂OH, CH₂CH₂OH;    -   R₂═H, CH₃, CF₃, Cl, Br; and    -   n is 1, 2, or 3.

In certain embodiments, the R₁ substituents will alter the in vivohalf-life of the drug. In certain embodiments, the R₂ substituentsenhance the H1 receptor binding affinity. In addition, the spacermolecule, e.g., the (CH₂)_(m) linker to the carboxylic acid group, canbe substituted with one or more substituents. In one embodiment, thespacer molecule is mono-substituted. In another embodiment of theinvention, the spacer molecule is disubstituted. In particularembodiments, the linkers of the invention may be geminally-dialkylated,e.g., gem-dimethylated, singly substituted with a substituent other thana noncyclic alkyl group, e.g., a heteroatom, or a cyclic substituentwherein one or more of the carbons of the spacer molecule is containedin the ring, e.g., heterocycle (e.g., tetrahydrofuran ortetrahydropyran), or cyclic alkyl, e.g., cyclopropyl. However, thesubstitution of the spacer molecule is independent of the substitutionat the R₁ and R₂ positions.

In specific embodiments of the invention which are directed todoxepin-like compounds, such that when R₁ and R₂ are both H, the alkylspacer molecule to the carboxylic acid is singly or doubly substitutedwith alkyl., including gem-dialkyl substitution, e.g., gem-dimethylsubstitution. In certain embodiments, the compound of the invention isnot a doxepin-like compound of Formula (V), wherein the alkylene spacermolecule is unsubstituted, and R₁ and R₂ are selected from the groupconsisting of H, halogen CF₃, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy. In anotherembodiment, R₁ and R₂ are not both H when the alkylene spacer moleculeis unsubstituted. In one embodiment, n is not 2 or 3 when the spacermolecule is unsubstituted.

Another embodiment of the invention is a pharmaceutical compositioncomprising a therapeutic compound as prepared according to themethodology of this invention, and a pharmaceutically acceptablecarrier.

In specific embodiments of the invention, the therapeutic compounds ofthe invention for treating CNS disorders, e.g., sleep disorders, areselected from Table 2. In certain embodiments, the therapeutic compoundsof the invention for treating CNS disorders, e.g., sleep disorders, areselected from Table 3. TABLE 2 Structure Series #

6a-HCl

6c-oxalate

6d-oxalate

6e-oxalate

6f-oxalate

15a-HOAc

15c-HCl

15d-oxa- late

15e-oxa- late

15f-oxa- late

11a-HCl

11c-HCl

11d-oxa- late

11e-HCl

11f-oxa- late

16a-HCl

16c-oxa- late

16d-oxa- late

16e-oxa- late

16f-oxa- late

13a-HCl

13c-oxa- late

13d-oxa- late

74a

N/A

N/A

D015a

D034a

204a

D102a

N/A

N/A

dox7a

6i-oxalate

5e-oxalate

5h-oxalate

5a-HCl

115a-HCl

D006a- HCl

13f-oxa- late

18a-Et3N

18c-oxa- late

18d

18e-oxa- late

18f

E,E-7a

E,E-7c- oxalate

E,E-7d- oxalate

E,E-7e- oxalate

E,E-7f- oxalate

E,Z-7c- oxalate

E,Z-7e- oxalate

E,Z-7f- oxalate

E-16a

E-16c- oxalate

E-16d- oxalate

E-16e- oxalate

E-16f- oxalate

dox7c- oxalate

dox7d- oxalate

dox7e- oxalate

dox7f- oxalate

75a

N/A

N/A

D035a

D024a

202a

D214a

N/A

N/A

53a

6h-oxalate

5f-oxalate

5i-oxalate

15k-oxa- late

55a-HCl

D-007a- HCl

8c-oxalate

8d-oxalate

8e-oxalate

8f-oxalate

E,E-10a

E,E-10c- oxalate

E,E-10d- oxalate

E,E-10e- oxalate

E,E-10f- oxalate

11e-oxa- late

15a-HCl

15g-oxa- late

15h-oxa- late

15i-oxa- late

11g-oxa- late

11h-oxa- late

11i-oxa- late

6g-oxalate

6i-oxalate

6h-oxalate

13e-oxa- late

8a

N/A

N/A

D003a- HCl

N/A

D014a

D025a

D104a

N/A

N/A

73a

16g-oxa- late

5d-oxalate

5g-oxalate

15j-oxa- late

113a-HCl

N/A

TABLE 3 Structure Series #

6a-HCl

6c-oxalate

16d-oxa- late

6e-oxalate

6f-oxalate

15a-HOAc

15c-HCl

15d-oxa- late

15e-oxa- late

11e-oxa- late

15a-HCl

15g-oxa- late

15h-oxa- late

15i-oxa- late

11g-oxa- late

11h-oxa- late

11i-oxa- late

6g-oxa- late

11c-HCl

11d-oxa- late

11e-HCl

11f-oxa- late

11a-HCl

6h-oxa- late

15f-oxa- late

6i-oxalate

In another embodiment, the invention is intended to include any novelcompounds, including compounds prepared as intermediates, describedherein. The scope of the present invention is also intended to includethe existence of stereocenters within the compounds of the invention,including compounds in both their racemic and stereoisomer enrichedforms. Additionally, the compounds described above are intended toinclude analogs containing art-recognized substituents that do notsignificantly effect the analog's ability to perform its intendedfunction. Furthermore, any novel synthesis of the compounds of theinvention described herein, is also intended to be included within thescope of the present invention.

Assays can be used to design and/or select compounds useful within thepresent invention. The SCORE method, described in Example 9, would be anexample of such an assay. Multiple assay components, such as total sleeptime, cumulative nonREM sleep profile, maximum nonREM sleep bout length,average nonREM sleep bout length, nonREM sleep time, nonREM onset ofaction profile, sleep latency, REM sleep time, REM sleep bout length,cumulative REM sleep profile, maximum wake bout length, average wakebout length, locomotor activity, locomotor activity intensity, bodytemperature, and drinking are used to define compounds that would beuseful in the present invention. For example, in determining therapeuticcompounds that would be useful as sedatives or wake-promoting compounds,all of the components listed above would be used in determining apreferred therapeutic compound. Antidepressant therapeutic compoundswould use the components of total sleep time, cumulative nonREM sleepprofile, maximum nonREM sleep bout length, REM sleep time, REM sleepbout length, locomotor activity, locomotor activity intensity, and bodytemperature for determination of preferred therapeutic compounds.

Exemplification of the Invention

The invention is further illustrated by the following examples thatshould not be construed as limiting.

Synthetic Preparation

Several synthetic protocols for compounds of the invention andintermediates thereto are shown below and are further depicted in theappropriate schemes. The compounds shall be herein referred to as Seriesin direct reference to the associated compound labeling number.

EXAMPLE 1 Synthesis of Antihistamine Intermediates

Several synthetic protocols for compounds of the invention are shownbelow and are further depicted in Scheme 2.

4-[diphenyl(hydroxy)methyl]-1-methylpiperidine (2). A solution ofbenzophenone (60 g, 0.33 mol) in anhydrous THF (200 mL) was addeddropwise over a period of 20 min to a Grignard reagent that was preparedfrom 59 g (0.44 mol) of freshly distilled 4-chloro-1-methylpiperidine,Mg (1.3 mol) in THF (1L). After stirring overnight, the reaction mixturewas quenched (H₂O, then dilute HCl) and extracted (2×500 mL) with ethylacetate. The combined organics were dried with Na₂SO4, filtered, andevaporated to dryness to give 89.5 g of alcohol 9. This alcohol was usedwithout further purification. The structure was confirmed by ¹H NMR.

4-(Diphenylmethylidene)-1-methylpiperidine (10). Alcohol 9 (27.3 g, 97mmol) was suspended in concentrated HCl (360 mL) and heated at reflux(oil bath temperature above 96° C.) for 2 h. The mixture was cooled inan ice bath followed by the addition of ethyl acetate (300 mL). Asolution of sodium hydroxide (200 g) in water (400 mL), cooled to 10°C., was added dropwise to the acidic mixture until the pH was 14. Ethylacetate (200 mL) was then added and the organic layer was separated andwashed with brine (200 mL). The combined aqueous layers were extractedwith ethyl acetate (2×300 mL). The combined organic layers were dried,filtered, and concentrated to give 23 g of the product as a brown oil.¹H NMR confirmed the structure of the product.

4-(Diphenylmethyl)-1-methylpiperidine (12). Solid sodium borohydride (6g, 160 mmol) and solid alcohol 9 (4.5 g, 16 mmol) were mixed to a fairlyhomogeneous solid mixture using a spatula. With rapid N₂ flow throughthe system, the solid mixture was added intermittently (cautiously andin small portions over a period of 45 min) to stirred trifluoroaceticacid (200 mL) cooled to 0° C. Extra caution was taken during theaddition of the NaBH₄ mixture to prevent localized heating and rapidbuild-up of pressure from the evolving and highly flammable H₂. Afterthe addition was complete, the reaction mixture was evaporated todryness. The above procedure was repeated using 5.2 g of 9 andproportional amounts of the other reagents. The combined residues fromthe two experiments were diluted with EtOAc/CH₂Cl₂ followed by theaddition of aqueous NaOH and then solid NaOH until the aqueous layermaintained a pH of 11. The organic layer was dried with Na₂SO₄,filtered, and evaporated to an oil that solidified. Chromatography oversilica gel using 10% MeOH/10% Et₃N in EtOAc gave 6.75 g of 12 as a whitecrystalline solid.

1-ethoxycarbonyl 4-(diphenylmethylidene)piperidine (19). Alkene-amine 10(23 g) was suspended in toluene (150 mL), whereupon dry potassiumcarbonate (13 g) was added. The mixture was then stirred for 15 minutes,filtered, and the filtrate concentrated to yield 18.5 g of purified1-methyl 4-(diphenylmethylidene)-piperidine. This purified material wasdissolved in dry toluene (100 mL), whereupon dry potassium carbonate (38g, 275 mmol) was added. Ethyl chloroformate (26.7 g, 245 mmol, 3.5equiv.) was added slowly with stirring and the mixture was heated atreflux overnight. The reaction mixture was cooled to room temperatureand the mixture was then filtered. The reaction vessel and filter cakewere subsequently washed with toluene (50 mL) and the filtered solid wasthen partitioned between water (125 mL) and ethyl acetate (100 mL).Stirring was required to dissolve the potassium carbonate within thesolid and the layers were subsequently separated. The organic layer wasdried with Na₂SO₄, filtered, and concentrated to yield 2.9 g of startingamine. The toluene layer obtained from washing the reaction vessel andthe filter cake was dried with Na₂SO₄, filtered, concentrated, and theresidue purified by flash chromatography (5/1 heptane/EtOAc) to yield11.47 g (51%) of 19. ¹H NMR confirmed the structure of the product andthe starting amine. (Carbamate 21 was similarly prepared.)4-(diphenylmethylidene)piperidine (2). Sodium hydroxide (15.85 g, 396mmol) in water (30 mL) was added to the carbamate 1-ethoxycarbonyl4-(diphenylmethylidene)piperidine 19 (11.47 g, 35.7 mmol) dissolved inethanol (150 mL). The mixture was heated at reflux overnight. Thereaction mixture was cooled to room temperature was then partitionedbetween water (100 mL) and ethyl acetate (150 mL). The mixture wasstirred to dissolve the solid and the layers were separated. The organiclayer was washed with brine (100 mL) and the separate aqueous layerswere extracted with ethyl acetate (100 mL). The combined organic layerswere dried with Na₂SO₄, filtered, and concentrated. The yellow oil wasdried by high vacuum to give 6.7 g (75%) of 20 as a yellow-white waxysolid. ¹H NMR was used to confirm the structure of the product. (Amine22 was similarly prepared.)

Synthesis of Antihistamines from Intermediates

Several synthetic protocols for the preparation of antihistamines fromthe synthetic intermediates described in Example 1 are shown below inExamples 2-5 and are further depicted in Scheme 3.

EXAMPLE 2 Pheniramine-like Series 11 Experimental

Isobutyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate (11e. Asolution of 20 (0.782 g, 3.14 mmol), isobutyl acrylate (0.56 mL, 3.89mmol) and ethanol (5 mL) was shaken at 75° C. for 2 h, then evaporatedto dryness to give 1.04 g of 11e as a viscous yellow oil that was usedwithout further purification. The structure was confirmed by ¹H NMR.(Propanoate esters 11b, 11c, and 11f were similarly prepared (seesynthesis of cyclopentyl acrylate in the Scheme 6).

Isopropyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate (1 d).Sodium hydride (60% dispersion in mineral oil, about 15 mg) was added toa stirred solution of 11b (1.20 g, 3.5 mmol) in 2-propanol (15 mL).Although after 1 h there was no insoluble solid, TLC showed evidence ofdegradation to the acid 11a, and the mixture was then stirred for anadditional 48 h. The mixture was concentrated, suspended in a smallamount of 1:1 heptane:ethyl acetate, filtered to remove insoluble solid(323 mg, 11a) and purified by flash chromatography to yield 560 mg (43%)of 11d. The structures were confirmed by ¹H NMR and LC/MS. (Propanoateester 11f was similarly prepared (this represents a second method forpreparing 11f).)

Cyclopentyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate, oxalicacid salt (1f-Ox). A solution of oxalic acid (190 mg, 2.11 mmol) inethanol (3 mL) was added in one aliquot to a stirred solution of 11f(885 mg, 2.26 mmol) in warm ethanol (5.5 mL). The mixture became solidafter 10 seconds of stirring. The solid mass was broken up and after 1.5h of stirring, the solid was collected by suction filtration and washedwith ethanol. After drying, the oxalate salt 11f-Ox was obtained aswhite powder (961 mg, 96%). ¹H NMR, MS, and elemental analyses wereconsistent with the structure of the product. (The oxalate salt of 11dwas similarly prepared.)

Ethyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate, HCl salt(11c-HCl). 2 M HCl/ether (1.45 mL) was added to a stirred solution of11c (812 mg, 2.32 mmol) in isopropyl ether (40 mL). After stirring for30 min, the resulting precipitate was filtered, washed with isopropylether, and recrystallized from boiling H₂O (2 mL) to give 608 mg of thehydrochloride salt of 11c-HCl as a creamy white powder. The structurewas confirmed by ¹H NMR, MS, and elemental analysis. (The HCl salt of11e was similarly prepared.)

The HCl salt of carboxylic acid Ha was prepared in a manner equivalentto that used to prepare 16a-HCl (see experimental for the 16 series).

EXAMPLE 3 Pheniramine-like Series 13 Experimental

Methyl 3-[4-(Diphenylmethyl)piperidin-1-yl]propanoate (13b). A solutionof methyl acrylate (699 mg, 8.12 mmol) in MeOH (3 m]L) was added to asolution of 22 (1.99 g, 7.92 mmol) in MeOH (8 mL). After shaking at 75°C. for 3 h, the reaction mixture was evaporated to dryness.Chromatography over silica gel (4:1 heptane/EtOAc) gave 2.54 g of 13b asa colorless viscous oil, which crystallized on standing. The structurewas confirmed by ¹H NMR. (Propanoate esters 13c and 13e were similarlyprepared.)

Isopropyl 3-[4-(D)iphenylmethyl)piperidin-1-yl]propanoate (1d. Adispersion of NaH (20 mg of a 60% oil dispersion) was added to asolution of 13b (799 mg, 2.37 mmol) in isopropyl alcohol (10 mL). Theresulting mixture was immediately stoppered tightly and stirred at RTfor 2 h. The reaction mixture was evaporated to dryness andchromatographed over silica gel using 3:1 heptane/EtOAc to give 0.75 gof 13d as a colorless viscous oil. The structure was confirmed by ¹HNMR. (Propanoate esters 13e and 13f were similarly prepared usingisobutanol and cyclopentanol, respectively (as mentioned above, 13e wasalso prepared by the previous method using isobutyl acrylate).)

Isobutyl 3-[4-(Diphenylmethyl)piperidin-1-yl]propanoate, oxalic acidsalt (3e-oxalate). A solution of oxalic acid (138 mg, 1.53 mmol) in H₂O(3 mL) was added to a stirred solution of 13e (583 mg, 1.54 mmol) inethyl alcohol (3 mL), whereupon no precipitate was formed. Evaporationto dryness gave a solid which was recrystallized from boiling isopropylalcohol to give 622 mg of the oxalate salt of 13e (13e-oxalate) as awhite crystalline solid. The structure was confirmed by ¹H NMR, MS, andelemental analysis. (Oxalate salts of 13c, 13d, and 13f were similarlyprepared.)

Carboxylic acid 13a was prepared in a manner equivalent to that followedto prepare 16a (see experimental for the 16 series).

EXAMPLE 4 Pheniramine-like Series 15 Experimental

Isopropyl [4-(diphenylmethylidene)piperidin-1-yl]ethanoate (od. Amixture of amine 20 (779 mg, 3.12 mmol), isopropyl bromoacetate (575 mg,3.18 mmol), K₂CO₃ (1.34 g, 3 eq), and acetonitrile (28 mL) was stirredat reflux overnight. The reaction mixture was filtered, evaporated todryness, and then chromatographed over silica gel using 5:1heptane/EtOAc to give 0.78 g of 15d as an oil that crystallized onstanding. The structure was confirmed by ¹H NMR. (Acetate esters 15b and15c were similarly prepared.)

Cyclopentyl [4-(diphenylmethylidene)piperidin-1-yl]ethanoate (15e). Asolution of 15b (1.02 g, 3.17 mmol) in anhydrous THF (10 mL) was added(under ND to a mixture of isobutyl alcohol (10 mL) and sodium hyride(258 mg of a 60% oil dispersion). After stirring for 1 h, the reactionmixture was partitioned between water and EtOAc, wherein a small amountof brine was added to prevent emulsion formation. The organic layer wasthen removed, the aqueous layer was extracted further with EtOAc, andthe combined organics were dried with Na₂SO4, filtered, and evaporatedto dryness. Chromatography over silica gel using 5:1 heptane/EtOAc gave0.8 g of 15e as an oil. (Acetate ester 15f was similarly prepared.)

Isopropyl [4-(diphenylmethylidene)piperidin-1-yl]ethanoate, oxalic acidsalt (15d-oxalate). A solution of oxalic acid (234 mg, 2.6 mmol) inethanol (4 mL) was added dropwise to a stirred solution of 15d (910 mg,2.6 mmol) in ethanol (12 mL). After cooling the reaction mixture to −15°C. for 15 min, the solid was filtered, washed with cold ethanol, andvacuum dried to give 891 mg of 15d-oxalate as a white crystalline solid.The structure of the product was confirmed by ¹H NMR, MS, and elementalanalysis. (The oxalate salts of 15c, 15e, and 15f were similarlyprepared.)

EXAMPLE 5 Pheniramine-like Series 16 Experimental

Methyl [4-(D)iphenylmethyl)piperidin-1-yl]ethanoate (1b. A mixture of 22(2.18 g, 8.68 mmol), methyl bromoacetate (1.44 g, 9.39 mmol),acetonitrile (40 mL), and K₂CO₃ (5.54 g, 4.6 eq) was stirred at refluxovernight, evaporated to dryness and chromatographed over silica gelusing 4:1 heptane/EtOAc to give 1.3 g of 16b as a white solid. Thestructure was confirmed by ¹H NMR. (Acetate esters 16c and 16d weresimilarly prepared.)

Isobutyl [4-(Diphenylmethyl)piperidin-1-yl]ethanoate (e). A mixture of16b (700 mg), isobutyl alcohol (10 mL), anhydrous THF (5 mL), and sodiumhydride (15 mg of a 60% oil dispersion) was prepared in a sealed vialand was shaken at 75° C. for 3 h, and subsequently poured over aH2O/EtOAc two-phase mixture. The aqueous layer was removed and extractedonce with EtOAc. The combined organics were dried with Na₂SO₄, filtered,and evaporated to dryness. Chromatography over silica gel using 5:1heptane/EtOAc gave 665 mg of 16e as a colorless oil. The structure ofthe product was confirmed by ¹H NMR. (Acetate ester 16f was similarlyprepared.)

Isobutyl [4-(Diphenylmethyl)piperidin-1-yl]ethanoate, oxalic acid salt(16e-oxalate). A mixture of oxalic acid (160 mg), 16e (650 mg), andisopropyl alcohol was evaporated to dryness. The resulting solid wasrecrystallized from boiling isopropyl alcohol to give 672 mg of theoxalate salt of 16e (16e-oxalate) as a white crystalline solid. Thestructure of the product was confirmed by ¹H NMR, MS, and elementalanalysis. (The oxalate salts of 16c, 16d, and 16e were similarlyprepared.)[4-(Diphenylmethyl)piperidin-1-yl]ethanoic acid, HCl salt (16a-HCl). Amixture of sodium hydroxide (6.1 g), water (25 mL), and THF (125 mL) wasshaken. One fourth of both the bottom and upper layers of the resultingbiphasic mixture was added to 747 mg of 16b (2.21 mmol). After stirringovernight, the reaction mixture was diluted with water and EtOAc andthen acidified with concentrated HCl. After removing the organic layer,the aqueous layer was extracted twice with EtOAc. The combined organicswere dried Na₂SO₄, filtered, evaporated to dryness, and moisture removedwith ethanol to give 801 mg of 16a-HCl as a glassy solid which wasscraped to a powder. ¹H NMR spectroscopy indicated that the solidconsisted of a 9:1 mixture of HCl and acetic acid salts of 16a.

Synthesis of Antihistamines

Synthetic protocols for the preparation of antihistamines of Series 6and 18 are shown below in Examples 6 and 7, respectively, and arefurther depicted in Schemes 4 and 5, respectively.

EXAMPLE 6 Diphenhydramine-like Series 6 Experimental

4-(diphenylmethoxy)-1-(ethoxyearbonyl)piperidine (a).4-(Diphenylmethoxy)-1-(methyl)piperidine (prepared by neutralization ofthe commercial HCl salt; 4 g, 14.2 mmol, 1 equiv.) in anhydrous toluene(20 mL) was stirred at room temperature under nitrogen. Ethylchloroformate (4.66 g, 43 mmol, 4.1 mL, 3 equiv.) was added dropwiseover 5 minutes, whereupon significant effervescence was noted. Themixture was heated over the course of 1 h to reflux with an oil bath(bath temperature 104° C.). The mixture was then cooled to roomtemperature, whereupon more ethyl chloroformate (4 mL) was added. Themixture was heated at reflux (bath T=104° C.) for 7 h and again cooledto room temperature. The cooled mixture was concentrated and the residuepurified by dry column chromatography (4×8.5 cm silica bed; 2:1heptane:ethyl acetate) to yield 3.49 g (72%) of 4a as a slightly yellowoil. ¹H NMR was consistent with the structure.

4-(diphenylmethoxy)piperidine (5).4-(Diphenylmethoxy)-1-(ethoxycarbonyl)piperidine (4a) (11.45 g, 33.7mmol) was dissolved in ethanol (72 mL). A cold solution of sodiumhydroxide (8.2 g, 205 mmol) in water (12 mL) was added slowly and asmall amount of heat was detected. The mixture was heated at reflux for17 h and then cooled to room temperature. The mixture was subsequentlydiluted with water (100 mL) and ethyl acetate (100 mL) and stirred for0.5 h to dissolve the resultant solid. The organic and aqueous layerswere separated and the organic layer was washed with water (100 mL). Theseparate aqueous layers were extracted with ethyl acetate (100 mL) andthe organic layers were combined, dried with Na₂SO₄, filtered andconcentrated to yield 7.88 g (87.5%) of 5 as a viscous yellow oil. Thestructure was confirmed by ¹H NMR.

Methyl 3-[4-(diphenylmethoxy)piperidin-1-yl]propanoate (6b). A solutionof 4-(diphenylmethoxy)piperidine (5 (1.4 g, 5.2 mmol), methyl acrylate(560 mg, 6.5 mmol) and methanol (9.5 mL) was placed on a preheatedorbital shaker at 75° C. for 3 h. The yellow solution was concentratedto yield 1.8 g (98%) of 6b as a yellow oil. The structure was confirmedby ¹H NMR. (The propanoate esters 6c and 6e were similarly prepared.)

Isopropyl 3-[4-(diphenylmethoxy)piperidin-1-yl]propanoate (6d). Oxalylchloride (7.27 g, 57.3 mmol, 5 mL) was added in one aliquot, withstirring, to a pre-cooled (ice bath) solution of 6a-HCl (1.14 g, 3.0mmol) in dry THF. Once the initial effervescence ceased, the flask wassealed under nitrogen and the mixture was stirred for 1.75 h. Themagnetic stirring bar was washed with dry THF upon its removal from thesolution mixture and the mixture was then concentrated on a rotaryevaporator to give a yellow-white solid. The solid was dried under highvacuum for 1 h. The solid was then suspended in 2-propanol (15 mL) and4-ethylmorpholine (440 mg, 400 μL, 3.8 mmol, 1.28 equiv.) was added.Vapors formed above the suspension and the slurry became anorange-yellow solution after about 2 minutes. After having been stirredfor 2.5 days, the reaction mixture was concentrated. The residue wasdissolved in dichloromethane (25 mL) and washed with 1 N KOH (15 mL).The layers were separated and the aqueous layer was extracted withdichloromethane (25 mL). Both organic layers were washed with water (25mL), combined, dried with Na₂SO₄, filtered and concentrated to yield 976mg (84%) of a dark orange-yellow oil. This oil was purified by flashchromatography (2:1 heptane:ethyl acetate) to yield 774 mg (67%) of 6das a yellow oil. ¹H NMR and LC/MS confirmed the structure. (Thepropanoate ester 6f was similarly prepared.)

Isopropyl 3-[4-(diphenylmethoxy)piperidin-1-yl]propanoate (6d),Alternate procedure. Sodium hydride (60% dispersion in mineral oil,about 15 mg) was added to a stirred solution of 6b (384 mg, 1.09 mmol)in 2-propanol (8 mL). Although after only 1 h there was no insolublesolid, TLC showed evidence of degradation to the acid 6a. Afterconfirmation by TLC that the reaction was complete, the mixture wasconcentrated and dissolved in a small amount of 2:1 heptane:ethylacetate for flash chromatography. The insoluble solid was isolated byfiltration (58 mg) and was shown to be 6a. The solution was purified byflash chromatography to yield 300 mg (72%) of 6d as a colorless oil.Purity (LC/MS): 99.6% (m/z381). (The propanoate ester 6f was alsoprepared by this alternate procedure.)

3-[4-(diphenylmethoxy)piperidin-1-yl]propanoic acid hydrochloride(a-HCl). A solution of sodium hydroxide (1.3 g, 32.5 mmol, 1.98 equiv.)in water (16 mL) was slowly added to a stirring solution of 6b (5.8 g,16.4 mmol) in methanol (58 mL) at room temperature, resulting in aslight increase in temperature. The solution was heated at reflux for1.25 h, cooled to room temperature, and concentrated. The resultingresidue was dissolved in water (75 mL) and the pH was adjusted to 2 withconcentrated HCl (about 2.5 mL). The thick mixture was then extractedwith chloroform (3×80 mL; 6a-HCl is soluble in chloroform) and thecombined organic layers were washed with brine (100 mL). The organiclayers were dried with Na₂SO₄, filtered, and concentrated to give 6a-HClas white needles (5.3 g, 86%). The structure was confirmed by ¹H NMR andLC/MS.Ethyl 3-[4-(diphenylmethoxy)piperidin-1-yl]propanoate, oxalic acid salt(6c-Ox). A solution of oxalic acid (130 mg, 1.44 mmol) in ethanol (3 mL)was added in one aliquot to a stirred solution of ethyl3-[4-(diphenylmethoxy)piperidin-1-yl]propanoate 6c (530 mg, 1.44 mmol)in ethanol (3 mL). The mixture became solid at the end of the addition,whereupon more ethanol (2 mL) was added to facilitate stinig. After 1 hof stirring, the solid was collected by suction filtration and washedwith ethanol (2 mL). After drying, the oxalate salt 6c-Ox was obtainedas white powder (595 mg, 90%). ¹H NMR, LC/MS, and elemental analysiswere consistent with the structure. (The oxalate salts of 6d, 6e, and 6fwere similarly prepared.)

EXAMPLE 7 Pheniramine Analog Series 18 Experimental

4-(3-dimethylamino-1-(2-pyridyl)propyl)benzoic acid (oa).(+/−)-Brompheniramine 17 (obtained, by neutralization of the maleatesalt; 38 g, 120 mmol) was dissolved in dry THF under nitrogen and thesolution was cooled in a dry ice/acetone bath. n-butyllithium (1.6 M,hexanes, 90 mL, 144 mmol) was added dropwise to the reaction mixture togive a red solution. After 2 h of stirring, carbon dioxide was bubbledinto the solution as the bath slowly warmed to room temperature. Theresulting mixture was stirred overnight and the reaction was quenchedwith water (500 mL). The aqueous layer was extracted with ethyl acetate(2×500 mL). The organic layer was discarded and the aqueous layer wasconcentrated to a yellow paste. The paste was digested in sodiumhydroxide (1 N, 150 mL) and chloroform (200 mL) and the layers wereseparated. The aqueous layer was extracted with chloroform (200 mL) andethyl acetate (2×150 mL). The chloroform layers were concentrated toyield unreacted 17 (17 g, 44%). The ethyl acetate layers wereconcentrated to 1.4 g of a complex mixture which was discarded. Theaqueous layer was concentrated to a thick oil, filtered to removeinsoluble solid, and dissolved in ethanol (100 mL) and water (40 mL).The pH was adjusted to 2 by the careful addition of concentrated HCl(about 17 mL). The resulting solution was concentrated, dissolved in 1:1methanol:ethanol, filtered to remove insoluble NaCl and concentrated toa brown oil (13 g). The oil was purified by column chromatography(8.5/1/0.5 CH₂Cl₂/MeOH/triethylamine) to yield 18a as a white solid (3g, 8%). The structure was confirmed by ¹H NMR, LC/MS, and elementalanalysis.

Ethyl 4-[3-dimethylamino-1-(2-pyridyl)propyl]benzoate (8c). Acid 18a(927 mg, 3.26 mmol) was stirred in oxalyl chloride (5 mL) at roomtemperature for 2 minutes and dry toluene (4 mL) was added to facilitatestirring. After 1 h, the mixture was concentrated. Ethanol (10 mL) andtriethylamine (1.35 mL) were added and the dark yellow mixture wasstirred overnight. The mixture was then concentrated and partitionedbetween ethyl acetate (25 mL) and water (25 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (10mL). The combined organic layers were washed with water (20 mL) and thecombined aqueous layers were extracted with ethyl acetate (20 mL). Thecombined organic layers were dried with Na₂SO₄, filtered, andconcentrated to yield 18c as an oil. Purification by flashchromatography (4/1 CH₂Cl₂/MeOH) yielded 18c (136 mg) as a yellow oil.The structure was confirmed by ¹H NMR and LC/MS. (Esters 18d, 18e, and18f were similarly prepared.)Ethyl 4(3-dimethylamino-1-(2-pyridyl)propyl)benzoate, oxalic acid salt(18c-Ox). A solution of oxalic acid (52 mg, 0.58 mmol) in ethanol (0.5mL) was added in one aliquot to a stirred solution of 18c (185 mg, 0.59mmol) in ethanol (0.5 mL). The mixture became solid after 30 seconds ofstirring. The solid mass was broken up, ethanol (0.75 mL) was added, andthe solid was collected by suction filtration after 1.5 h of stirringand subsequently washed with ethanol. After drying, the oxalate salt18c-Ox was obtained as white powder (167 mg, 72%). ¹H NMR, LC/MS, andelemental analyses were consistent with the structure of the product.(The oxalate salt of 18e was prepared similarly.)

Synthesis of Triprolidine Series

Synthetic protocols for the preparation of the triprolidine series areshown below in Examples 8 and are further depicted in Scheme 6.

EXAMPLE 8 Triprolidine-like Series 7 Experimental

6-Bromo-2-pyridyl 4-tolyl ketone (3). A solution of 1 (50.02 g, 0.211mol) was added to a stirred and cooled (−78° C.) solution of 1.6 Mn-BuLi/hexanes (132 mL) over a period of 1 h and 20 min. After anadditional 15 min at −78° C., a solution of p-tolunitrile (25.64 g,0.219 mol) in anhydrous THF (100 mL) was added rapidly (4 min) and thereaction mixture was stirred for another 4.75 h. During this time thetemperature was controlled to rise slowly from −78° C. to −20° C. Thereaction was stirred at room temperature overnight and then quenched bythe addition of 2 N HCl (500 mL). The organic layer was dried withNa₂SO₄, filtered, and evaporated to a solid. Recrystallization fromboiling ethanol gave 36.74 g of ketone 3 as an off-white crystallinesolid. The structure of the product was confirmed by ¹H NMR.

Cyclopentyl acrylate. Acryloyl chloride (75 mL) was added to a stirredsolution of cyclopentanol (88 g, 1 mol) and triethylamine (175 mL) indry THF (500 mL) at a rate slow enough to prevent overheating of thereaction. The reaction mixture was allowed to stand overnight, filteredthrough a pad of Celite, evaporated to an oil, and distilled to givecyclopentyl acrylate as a colorless liquid (bp 74-79/˜60 mm Hg). Thestructure of the product was confirmed by ¹H NMR.

Ethyl (E)-3-[6-(4-toluoyl)-2-pyridyl]acrylate (5c). A mixture of ketone3 (16.90 g, 61.2 mmol), triphenylphosphine (1.64 g, 6.25 mmol),tributylamine (15 mL), and ethyl acrylate (16 mL) was stirred and heated(hot bath at 125-135° C.) for 7 h. Two additional aliquots of ethylacrylate (7 mL each) were added at 4h and 6h. After the reaction wascooled to room temperature, the reaction mixture was poured over water(300 mL) and EtOAc (300 mL). The aqueous layer was extracted furtherwith EtOAc. The combined organics were dried with Na₂SO₄, filtered, andevaporated to dryness. Chromatography over silica gel usingheptane/EtOAc (starting at 8:1) gave 15.49 g of 5c as a yellowcrystalline solid. The structure was confirmed by ¹H NMR.(Keto-acrylates 5e and 5f were similarly prepared using isobutylacrylate and cyclopentyl acrylate, respectively.)

(2-pyrrolidinoethyl)triphenylphosphonium bromide. A mixture of2-phenoxyethyl bromide (90.6 g, 0.45 mol), triphenylphosphine (119.2 g,0.45 mol), and phenol (854 g) was heated to a melt and then stirred overa hot oil bath (107-114° C.) for ˜24 h. The reaction mixture wasextracted with 6:1 heptane/EtOAc (3×2 L), 9:1 heptane/EtOAc (3×0.5 L),and heptane (300 mL) to give an oil that solidified. After dissolvingthe reaction mixture in DMSO, the mixture was warmed, treated withpyrrolidine (150 mL), and stirred over a hot oil bath (50-55C) for 1.5h. The reaction mixture was cooled to room temperature, seeded forcrystallization, and treated slowly and intermittently with increasingamounts of t-butyl methyl ether (TBME) until it was evident thatcrystallization was complete. The solid was filtered, washed with TBMEand then with heptane, and vacuum dried to give 90.27 g of the desiredproduct. The structure was confirmed by ¹H NMR.

Triprolidine E,E-7c. A solution of 25 mL of 1.6 M n-BuLi/hexanes wasadded to a stirred and cooled (0° C.) suspension of(2-pyrrolidinoethyl)triphenylphosphonium bromide (17.24 g, 39.18 mmol)in dry THF (250 mL) over a period of ˜4 min. The ylide-forming reactionmixture was stirred an additional 10 min at 0° C., followed by theaddition of one aliquot of a solution of 5c (4.52 g, 15.3 mmol) in dryTHF (75 mL). After stirring at 0° C. for only 2 min, the reactionmixture was quenched by the addition of water (100 mL). The reactionmixture was then extracted twice with EtOAc and the combined organicswere dried with Na₂SO₄, filtered, and evaporated to dryness.Chromatography over silica gel using MeOH/EtOAc (starting at 5% MeOH)gave 1.42 g (25%) of E,E-7c as a yellow crystalline solid and 2.42 g(42%) of E,Z-7c. The structure of the products were confirmed by ¹H NMRand MS. (Triprolidine ester E,E-7e was similarly prepared.)

Triprolidine E,E-7f. Sodium hydride (25 mg of a 60% oil dispersion) wasadded to a solution of E,E-7c (1.116 g, 2.96 mmol) in cyclopentanol (10mL) and dry THF (8 mL). After stoppering the reaction flask, thereaction mixture was stirred at room temperature for 1.5 h and quenchedby the addition of saturated brine (30 mL). The mixture was extractedtwice with EtOAc and the combined organics were dried with Na₂SO₄,filtered, and evaporated to dryness. Chromatography over silica gelusing MeOH/EtOAc (starting at 2% MeOH) gave 1.04 g of the desiredproduct as a viscous oil. The structure of the product was confirmed by¹H NMR. (Triprolidine esters E,E-7d was similarly prepared.)

Triprolidine E,E-7e-oxalate. A solution of oxalic acid (362 mg, 4 mmol)in ethanol (4 mL) was added to a stirred solution of E,E-7e (1.63 g) inEtOH. After evaporating to dryness, the resulting oil was dissolved inEtOAc and again evaporated to dryness, whereupon a solid was generated.Recrystallization from boiling EtOAc gave 1.59 g of the oxalate salt ofas an off-white powder. The structure was confirmed by ¹H NMR,MS, and elemental analysis. (The oxalate salts of the E,E-isomers of 7c,7d, and 7f were similarly prepared.)

Triprolidine acid E,E-7a was prepared in a manner similar to that usedto prepare acids 11a, 13a, 15a, and 16a described above.

EXAMPLE 9 Doxepin-like Series Experimental

Step 1:

A mixture of THF (150 mL) and N,N,N′,N′-tetramethylethylenediamine (27.8mL, 0.1853 mol, 2.5 eq.) was cooled to −78° C. s-Butyllithium (0.2 mol)was added slowly (40 min) maintaining the temperature between −65 to−78° C. After an additional 20 min stirring, 4-chlorobenzoic acid (11.60g, 0.0741 mol, 1.0 eq.) dissolved in TBF (150 mL) was added over aperiod of 60 minutes while maintaining the temperature between −65 to−78° C. After 2 h, iodomethane added, and stirring continued for 1 hour,at which time the cooling bath was removed. Water (164 mL) was addedslowly and the reaction mixture was allowed to warm to room temperature.The layers were then separated, and the aqueous layer was washed withtert-butyl methyl ether (3×100 mL), and acidified with HCl to pH 1-2.The product was subsequently collected by filtration, washed with water,and dried under vacuum at 60° C. to give compound 2 (10.63 g, 84.0%). ¹HNMR was consistent with the structure.Step 2:

Compound 2 (10.62 g, 62.3 mmol, 1.0 eq.) was dissolved in methanol (200mL) and thionyl chloride (11.3 mL, 155.25 mmol, 2.5 eq.) was addedslowly. The reaction solution was refluxed for 5 h, the solvent wasremoved, and the oil was taken up in methylene chloride (200 mL). Theorganic layer was washed with H₂O (3×100 mL), dried over MgSO₄,filtered, concentrated, and dried to give compound 3 (10.86 g, 94.4%).The structure was confirmed by ¹H-NMR.Step 3:

Compound 4 (10.86 g, 58.8 mmol, 1.0 eq.) was dissolved in carbontetrachloride (100 mL), and N-bromosuccinimide (15.7 g, 88.2 mmol., 1.5eq.) was added followed by benzoylperoxide (0.05 g). The mixture wasrefluxed overnight. The reaction mixture was then filtered, and thesolids were washed with dichloromethane. The combined organic filtratewas concentrated and dried to give compound 4 (7.1 g, 45.8%). Thestructure was confirmed by ¹H NMR.Step 4:

Phenol (2.79 g, 29.63 mmol, 1.1 eq.) was dissolved in 2-butanone (75.0mL) and potassium carbonate (11.17 g, 80.82 mmol., 3.0 eq.) was added,followed by compound 4 (7.1 g, 26.94 mmol., 1.0 eq.) dissolved in2-butanone (75.0 mL). A catalytic amount of potassium iodide (0.05 g)was added and the mixture was refluxed overnight. The cooled reactionmixture was filtered and the solids were washed with 2-butanone. Thecombined filtrate was taken up in ethyl acetate (75 mL) and was washedwith 5% aqueous NaOH (2×50 mL), brine (40 mL), and water (50 mL). Theorganic phase was concentrated and purified on silica gel to givecompound 5 (9.32 g). The structure confirmed product by ¹H NMRStep 5:

A solution of NaOH (4.0g, 3.0 eq.) in H₂O (20 mL) was added to compound5 (9.32 g, 1.0. eq.) dissolved in MeOH (50 mL), and refluxed for 45 min.After cooling, the solvent was removed, H₂O added (100 mL), and aqueouslayer (aq. Extract-1) washed with ethyl acetate. The product wasextracted into the ethyl acetate layer. The organic phase was thenwashed with water/5% NaOH (3×75 mL) (aq. Extract-2). Each of the aqueousextracts 1 and 2 (which were not combined) was acidified to pH 1-2 withHCl. The white precipitate obtained was taken up in dichloromethane(3×75 mL). After removal of the solvent and drying, aq. Extract-1 gave1.61 g solid containing some product but mostly compound 1, and aq.Extract-2 gave 5.68 g product (compound 6). The structures wereconfirmed by ¹H NMR.Step 6:

Compound 6 (6.0 g, 22.84 mmol., 1.0 eq.) was dissolved indichloromethane (75.0 mL) and trifluoroacetic anhydride (7.2 g, 34.26mmol., 1.5 eq.) was added, followed by a catalytic amount ofborontrifluoride etherate (0.4 mL). Reaction mixture was heated to 40°C. for 4 h. The reaction mixture was washed with water (50 mL),saturated NaHCO₃ (2×50 mL), and water (50 mL). The organic phase wasdried over MgSO₄, filtered and concentrated. The crude product waspurified on 120 g RediSep column using gradient elution,heptane/ethylacetate to give compound 7 (3.69 g, 66.0%). The structurewas confirmed by ¹H NMR and LC/MS.Step 7:

The ketone 7, was subjected to McMurray reaction. Accordingly, titaniumchloride (4.05 mL, 36.85 mmol.) was slowly added to a mixture of zincdust (5.31 g, 81.2 mmol., 5.4 eq.) in anhydrous THE (60 mL) at 0° C. Themixture was then refluxed for 2.5 hours. N-carbethoxy-4-piperidone, (5.5mL, 36.3 mmol., 2.4 eq.) and ketone 7 (3.69 g, 15.12 mmol., 1.0 eq.)were dissolved in anhydrous THF (40.0 mL) and added to the titanium (0)mixture, and the reaction mixture was refluxed for 6 h. An aq. solutionof K₂CO₃ (150 mL of 10% aqueous solution) was then added and stirred for30 min. The mixture was subsequently filtered over pad of celite, andthe solids were washed with ethylacetate. The layers were separated andthe organic phase was collected, dried over MgSO₄, and concentrated togive the compound 8 (8.15 g, 80.0% pure by HPLC). The structure wasconfirmed by ¹H NMR and LC/MS.Step 8:

Compound 8 was dissolved in ethanol (60.0 mL), and an aq. solution ofsodium hydroxide (10.2 g, 254.76 mmol., 12.0 eq.) in H₂O (15.0 mL) wasadded and refluxed overnight. The solids were filtered off, and thenwashed with ethanol. The filtrate was concentrated and the oily residuewas taken up in dichloromethane (155 mL) and H₂O (40 mL). The aqueouslayer was extracted with CH_(2 Cl) ₂ (3×50 mL) and combined with theorganic layer. The combined organic phase was washed with brine, driedover NaSO₄, filtered and concentrated to give 3.95 g of crude compound9. The structure of compound 9 was confirmed by H NMR and LC/MS and thecrude material was taken to the next step without purification.Step 9:

Compound 9 (2.0 g, 6.41 mmol., 1.0 eq.), K₂CO₃ (1.77 g, 12.82 mmol., 2.0eq.), halide (5.28 g, 32.05 mmol., 5.0 eq.) and DMF (25.0 mL) werecombined and heated to 100° C. overnight. The crude reaction mixture wasmixed with H₂O (30 mL) and CH₂Cl₂ (35 mL). The organic phase wasseparated and the aqueous phase was washed with CH₂Cl₂ (2×25 mL). Thecombined organic phase was washed with brine and concentrated. The crudematerial was purified on a silica column to give compound 10 (1.2 g).The structure was confirmed by ¹H NMR and LC/MS.Step 10:

Compound 9 (2.0 g, 6.41 mmol, 1.0 eq.), aldehyde (1.7 g, 13 mmol, 2.0eq.) and CH₂Cl₂ (20 mL) were taken in a flask under nitrogen and cooledto 0° C. Na(OAc)₃BH (2.6 g, 12.32 mmol, 1.9 eq.) was added in controlledaliquots and stirred at 0° C. for 30 min. the reaction mixture wasallowed to reach room temperature and stirred overnight. The mixture wasthen diluted with CH₂Cl₂ (40 mL), an aq. solution of satd. NaHCO₃ (30mL) was subsequently added, and the reaction mixture was stirred for 10min. The organic phase was separated and the aq. phase was extractedwith CH₂Cl₂ (2×25 mL). The combined organic layer was dried (NaSO₄),concentrated, and the crude material was purified on a silica column togive compound 11 (1.72g). The structure was confirmed by ¹H NMR andLC/MS.Step 11:

Compound 11 (1.6 g, 3.76 mmol, 1 eq.) was dissolved in ethanol (40.0mL). An aq. solution of sodium hydroxide (2.0 g, 50 mmol., 13.0 eq.) inH₂O (9.0 mL) was added and refluxed overnight. The solids were filteredoff, and the solvents were then distilled off. The residue was taken upin H₂O (40 mL) and acidified with HCl to pH 1 and stirred for 20 min.The resulting solids were filtered, washed with heptane, and dried underhigh vacuum to give the compound 12 (1.59 g). The structure of thecompound 12 was confirmed by ¹H NMR, LC/MS and elemental analysis.

Schemes 7 through 15, shown below, depict the synthesis of severaldoxepin-like compounds of the invention, with various degrees ofsubstitution (i.e., various substituents at the R₁ and R₂ positions, onthe spacer molecule, and combinations thereof)

EXAMPLE 10

Sleep-wakefulness, locomotor activity and body temperature weremonitored in Male Wistar rats treated with three chemical formulations,individually including three antihistamine-class compounds of theinvention, 11f, 15f, and 6f. Treatments were administered at CT-18(Circadian Time, 6 hours after lights-off) and produced robust soporificeffects characterized by increased nonREM sleep time, increased sleepcontinuity, but without evidence of REM sleep inhibition or reboundinsomnia. The general experimental conditions utillized in testing theabove listed compounds of the invention are described below.

I. Animals & Surgery. Adult, male Wistar rats (250 g at time of surgery,Charles River Laboratories) were anesthetized (Nembutal, 62 mg/kg) andsurgically prepared with a cranial implant to permit chronicelectro-encephalogram (EEG) and electromyogram (EMG) recording. Bodytemperature and locomotor activity were monitored via a miniaturetransmitter (Minimitter) surgically placed in the abdomen. The cranialimplant consisted of stainless steel screws (two frontal [+3.2 AP frombregma, ±2.0 ML] and two occipital [−6.9 AP, ±5.5 ML]) for EEGrecording. Two Teflon-coated stainless steel wires were positioned underthe nuchal trapezoid muscles for EMG recording. All leads were solderedto a miniature connector prior to surgery, and gas sterilized inethylene oxide. The implant assembly was affixed to the skull withdental acrylic. A minimum of three weeks was allowed for surgicalrecovery.

II. Recording environment. Each rat was permanently housed in its ownindividual recording cage located within separate, ventilatedcompartments of custom-designed stainless steel cabinets. Each Nalgenemicroisolator cage was enhanced with a filter-top riser and low-torqueswivel-commutator. Food and water were available ad libitum. A 24-hrlight-dark cycle (12 hours light, 12 hours dark) was maintainedthroughout the study using 4-watt fluorescent bulbs 5 cm from the cage.Animals were undisturbed for at least 48 hours before and aftertreatments.

III. Automated physiological monitoring. Sleep and wakefulness weredetermined using “SCORE-2000™”—an internet-based sleep-wake andphysiological monitoring system. The system monitored amplified EEG(bandpass 1-30 Hz; digitization rate 400 Hz), integrated EMG (bandpass10-100 Hz), body temperature and non-specific locomotor activity (LMA)via telemetry, and drinking activity, continuously and simultaneously.Arousal states were classified on-line as NREM sleep, REM sleep, wake,or theta-dominated wake every 10 seconds using EEG feature extractionand pattern-matching algorithms. The classification algorithm usedindividually-taught EEG-arousal-state templates, plus EMG criteria todifferentiate REM sleep from theta-dominated wakefulness, plusbehavior-dependent contextual rules (e.g., if the animal was drinking,it is awake). Drinking and locomotor activity (LMA) were recorded asdiscrete events every 10 seconds, while body temperature was recordedeach minute. Locomotor activity was detected by a telemetry receiver(Minimitter, Sunriver, Oreg.) beneath the cage. Telemetry measures (LMAand body temperature) were not part of the scoring algorithm; thus,sleep-scoring and telemetry data were independent measures.

Iv Treatments and Study Design.

-   -   A. Timing of treatment. Compounds were administered at CT-18,        the peak of the activity-dominated period, in order to        ensure (i) prior wakefulness was sufficient to interact        positively with hypnotic-drug effects, and (ii) sufficient time        was allowed to view the time course of the treatment effect        before lights-on (6 hours post-treatment).    -   B. Vehicle and route of administration. Compounds were suspended        in sterile 0.25% or 0.5% methylcellulose (2 ml/kg). Treatments        were administered as an intraperitoneal bolus.    -   C. Study design and controls. A parallel group study design was        employed. Vehicle controls were drawn from a large pool (N>200):        a subset of the pooled vehicle controls was selected, based on        computerized matching with the 24-hour pre-treatment baseline of        the active treatment group.    -   D. Drugs tested. Three (3) antihistaminergic novel chemical        compounds of the current invention were tested for this proof of        principle study, 11f (30 and 10 mg/kg), and 6f (30 mg/kg) and        15f (30 mg/kg).

Results of Compounds Tested

11f significantly increased total sleep time for 3 hours post-treatmentafter both 30 mg/kg and 10 mg/kg treatments (N=11 and 9, respectively,where N is the number of animals per dose group), and increased sleepcontinuity, as assessed by sleep bout length. The effect on maximumsleep bout length (a measure of sleep continuity) during the initial 5hours post-treatment sleep bout versus dose is shown in FIG. 1(c). 11fincreased sleep continuity at both 10 and 30 mg/kg doses relative tovehicle control. The treatment effects of Zolpidem are also shown forcomparison.

A concomitant reduction in locomotor activity paralleled the sleepinducing effects of 11f. These effects were prototypical forsedative-hypnotic/soporific agents and compared equal or better totherapeutic doses of the sedative hypnotic market leader—Ambien®(Zolpidem). 11f did not, however, produce REM sleep inhibition orrebound insomnia at 10 mg/kg or 30 mg/kg in male Wistar rats. REM sleepinhibition and rebound insomnia are undesirable side effects commonlyobserved in currently marketed prescription sedative hypnotics. Acomparison of the total sleep time resulting from 11f (30 mg/kg), thesedative hypnotic positive control standard (Zolpidem, 10 mg/kg), andthe vehicle control as a function of time from the administration of thedose is depicted as a time series plot in FIG. 1(a). The time seriesplot shows the sleep patterns before and after treatment, wherein thearrow indicates the primary soporific effect of 11f.

The cumulative effect on total sleep time (TST) during the initial 5hours post-treatment, relative to baseline (BL), for 11f (HY2325),Zolpidem, and the vehicle control is shown in FIG. 1(b). It is apparentthat 11f (30 mg/kg) induced more TST than Zolpidem (10 mg/kg).

6f (N=5) and 15f (N=5), compounds of the invention related to HY2325-01,also produced an increase in nonREM sleep time for 2-3 hourspost-treatment relative to the vehicle control animals. In addition, 6fand 15f did not produce REM sleep inhibition or rebound insomnia underthe conditions studied.

11f, 6f and 15f, are representative novel antihistaminergic soporificchemical compounds of the invention. 11f increased sleep, e.g., sleeptime and sleep continuity (sleep bout lengths), in laboratory rats in adose-dependent fashion. Single doses of 6f and 15f also increased sleepin laboratory rats.

Additional compounds of the invention were tested using the abovemethodology, and the results are shown below in Table 4.

TABLE 4 Average Maximum Bout- Bout NREM NREM Compound Dose OnsetDuration Length Length Peak Accum. Rebound Motor REM at CT-18) (mg/kg)(minutes) (hrs) (minutes) (minutes) (%/hr) (minutes) Insomnia InhibitionInhibition Ambien 30 IP 5 3-4 5.8 13.1 58.2 58.7 YES YES YES (Zolpidem)Doxepin-like 30 PO 90 4-5 11 25.1 72.0 44.8 NO NO YES (8a) 30 PO 65 5-612.2 28.9 75.5 65.8 NO NO NO (73a) 30 PO 45  5-6+ 14.5 27.6 62.2 47.3 NONO NO (74a) 30 PO 70-80 5-6 9.9 22.3 64.4 43.4 NO NO NO (75a) 30 PO70-85 4 6.8 13.6 58.8 33.9 NO NO NO (75a) 45 PO 70-85 5 10.8 19.4 58.233.9 NO NO NO (7a) 30 PO 130 5-6 7.3 16.9 56.9 29.5 NO NO NO (7d) 30 PO85 5 12.9 25.0 76.9 54.1 NO NO NO Pheniramine-like (11a) 30 PO 85 6 11.218.7 67.3 41.2 Minor NO NO (11d) 30 PO 135 6 11.0 20.1 58.5 55.5 NO NONO (11e) 30 PO 80 6 8.3 19.1 59.6 49.6 NO NO NO Diphenhydramine-like(53a) 30 PO 30 4 4.3 9.1 49.2 17.4 NO NO NO (6a) 30 PO 65 5 7.0 12.856.4 26.5 NO NO NO Triprolidine-like (16a) 30 PO 180 5 5.4 11.8 57.920.7 NO NO NONote:Po is oral administration and IP is intraperitoneal administration.

EXAMPLE 11 H1 Binding Assay For Series 11 Compounds

I. Introduction

The following binding assays were performed on the Series 11 compoundsdescribed above by displacement of known standards from the H1, M1, M2,and M3 receptors, wherein H1 is a histamine receptor, and M1, M2, and M3are muscarinic receptors.

The binding studies against the histamine receptor, H1, indicate bindingaffinity, and therefore the results of the binding assays are anindication of the activity of the compound.

In addition, the binding studies against the muscarinic receptorsindicate the extent to which the compounds bind the muscarinicreceptors, responsible for anti-cholinergic activity of the compound.Binding to muscarinic receptors results in several undesired sideeffects of many known antihistamines, e.g., dry-mouth. A decrease in thebinding of the compounds to the M1-M3 receptors, relative the binding ofthe compound to the H1 receptor, is an indication of the greaterspecificity of the compound for the histamine receptor over themuscarinic receptor. Moreover, a drug with increased specificity for thehistamine receptor would possess less anti-cholinergic side effects.

III. Results

The data in Table 5 show the results of the assays, described above,performed on the Series 11 compounds, as indicated. TABLE 5 H1 M1 M2 M3Compound number IC50 Ki IC50 Ki IC50 Ki IC50 Ki Acid 11a 3.08E−71.19E−7 >1.0E−5 >1.0E−5 >1.0E−5 >1.0E−5 >1.0E−5 >1.0E−5 Isopropyl 11d3.78E−7 1.47E−7 8.00E−6 6.96E−7 8.29E−7 2.70E−7 6.08E−6 2.70E−6 Isobutyl11e 7.18E−7 2.79E−7 3.76E−6 2.89E−7 3.55E−6 1.15E−6 2.59E−6 7.10E−7Cyclopentyl 11f 1.07E−6 4.16E−7 2.21E−6 1.70E−7 — — — — S-THF 11g1.96E−7 8.61E−8 4.68E−6 3.60E−7 5.70E−6 2.08E−6 5.71E−6 1.56E−6 R-THF11h 2.01E−7 8.83E−8 2.24E−6 1.72E−7 2.14E−6 6.97E−7 2.20E−6 6.03E−7 THP11i 2.00E−7 8.78E−8 2.21E−7 1.70E−8 2.21E−7 7.20E−8 2.33E−6 1.03E−6IV ConclusionsA. An interesting trend that is exhibited by the data in Table 4, showsthat the tetrahydrofuran and tetrahydropyran esters appear to show agreater affinity for the H1 receptor than the non-oxygen substitutedesters.

This increased affinity may be an indication of increased watersolubility or that the altered ring conformation may have any affect onthe steric properties at the carbonyl of the ester, e.g., a beneficialchange in the ring conformation due to the presence of the oxygen.Alternatively, the presence of the oxygen may lend itself to alterationof the physical properties of the molecule in other ways, e.g., theelectronic properties help to control ester cleavage, or the presence ofthe oxygen adds to receptor affinity through increased bindinginteractions with the receptor.

B. In addition the data indicates that the compounds have greateraffinity for the H1 receptors as compared with the M1, M2, and M3receptors, which as described above, indicates that these drugs shouldresult in the reduction of anti-cholinergic side effects.

C. Table 4 also indicates that the binding data for the enantiomericcompounds, 11h and 11g, do not result in a substantial difference inbinding affinity towards the H1 receptor, but do show a substantialdifference in binding affinity towards the muscarinic receptors. Thisindicates that the muscarinic receptors may have a stereochemicalpreference, and therefore the selectivity of the receptor may be used toassist in the selection of a therapeutic compound that would providereduced side effects.

D. In addition, it can be seen in from the data in Table 4 that thecorresponding acid of the therapeutic ester compound loses detectableaffinity for the muscarinic receptors. This property, as describe above,can be used to reduce anti-cholinergic side-effects of the therapeuticcompound.

EXAMPLE 12 H1 Binding Assaysfor Additional Compound Series

I. Introduction

The following binding assays were performed on additional compoundsdescribed above by displacement of known standards from the H1, M1, M2,and M3 receptors, wherein H1 is a histamine receptor, and M1, M2, and M3are muscarinic receptors.

The binding studies against the histamine receptor, H1, indicate bindingaffinity, and therefore the results of the binding assays are anindication of the activity of the compound.

In addition, the binding studies against the muscarinic receptorsindicate the extent to which the compounds bind the muscarinicreceptors, responsible for anti-cholinergic activity of the compound.Binding to muscarinic receptors results in several undesired sideeffects of many known antihistamines, e.g., dry-mouth. A decrease in thebinding of the compounds to the M1-M3 receptors, relative the binding ofthe compound to the H1 receptor, is an indication of the greaterspecificity of the compound for the histamine receptor over themuscarinic receptor. Moreover, a drug with increased specificity for thehistamine receptor would possess less anti-cholinergic side effects.

II. Binding Assays

The binding assays for H1 was the same as described in Example 10 andthe M1, M2, and M3 binding assays are the same as those described inExample 10 for human recombinant expressed cells.

III. Results

The data in Table 6 show the results of the assays, described above,performed on various compounds of the invention, as indicated. TABLE 6H₁ Antagonist Series Receptor Binding Data (K_(i) nM) H₁ M₁ M₂ M₃Doxepin-like (8a) 62.5 >10,000 >10,000 >10,000 (73a)42.8 >10,000 >10,000 >10,000 (74a) 109 >10,000 >10,000 >10,000 (75a)47.9 >10,000 3,331 >10,000 (7a) 55.1 >10,000 >10,000 >10,000(dox7d-oxalate) 198 >10,000 >10,000 >10,000 Diphenhydramine-like (53a)16.1 >10,000 >10,000 >10,000 (6a) 56.1 >10,000 >10,000 8,900Triprolidine-like (16a) 43.9 >10,000 >10,000 >10,000IV Conclusions

The data indicates that the compounds have greater affinity for the H1receptors as compared with the M1, M2, and M3 receptors, which asdescribed above, indicates that these drugs should result in thereduction of anti-cholinergic side effects.

EXAMPLE 13 Determination of Receptor Selectivity

In one embodiment of the present invention, the selectivity for H1 isincreased relative other receptors (i.e., resulting highly soporificcompounds with fewer unwanted side effects from binding at adrenergic,muscarinic, serotonergic, and other receptors).

In this regard, a binding assay comparison of (8a), a doxepine-likecompound, was performed using a variety of receptor types, shown belowin Table 7, to determine receptor selectivity. As is evident from theresults shown below the selectivity of (8a) for H1 is dramaticallyimproved over the precursor molecule doxepin. TABLE 7 Percent Inhibition(1.0E−6) Receptor Doxepin (8a) Adrenergic, Alpha 1, Non-selective 92.11.7 Adrenergic, Alpha 2, Non-selective 53.5 −1.8 Histamine, H1 100.589.1 Histamine, H2 74.7 33.4 Muscarinic, M1 (Human Recombinant) 88.9 3.3Muscarinic, M2 (Human Recombinant) 74.0 8.2 Muscarinic, Non-selective,Central 95.2 4.4 Muscarinic, Non-selective, Peripheral 88.4 15.0Norepinephrine Transporter 97.8 −3.9 Serotonin Transporter 75.3 9.3Serotonin, Non-selective 68.4 17.0 Sigma, Non-selective 52.5 −2.9 HERG23%** 4%**Seldane, etc. = 100%

REFERENCES

-   1. Chem. Pharm. Bull. 1994, 42(11), 2276-2284 and 2285-2290.-   2. Synthesis 1976, 172-176.-   3. J. Labeled Compds. and Radiopharmaceuticals 1995, 36(10),    973-979.-   4. J. Pharmaceutical Sci. 1984, 73(10), 1339-1344.    Incorporation by Reference

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1-232. (canceled)
 233. A method of treating a sleep disorder, comprisingadministering to a subject an effective amount of a therapeuticcompound, such that the sleep disorder is treated, wherein thetherapeutic compound comprises the formula:[AH]−(SP)_(n) −[DA] wherein AH is a moiety that antagonizes a histaminereceptor or a collection of histamine receptors, DA is a drug activitymodulating moiety that provides the ability to modulate the activity ofthe therapeutic compound, selected from an ester, an alcohol, or anacid, and SP is a spacer molecule, (CH₂)_(m), where m is 1 to 20, and nis 0 or
 1. 234. The method of claim 233, wherein the DA does notsubstantially effect the biological activity of said AH compound. 235.The method of claim 233, wherein the DA significantly effects thebiological activity of said AH compound.
 236. The method of claim 235,wherein the DA improves the biological activity of said AH compound.237. A method of treating a sleep disorder, comprising administering toa subject an effective amount of a therapeutic compound of claim 233,such that the sleep disorder is treated, wherein the therapeuticcompound has a favorable biological property (FBP).
 238. The method ofclaim 237, wherein the FBP is selected from the group consisting ofpenetration through the blood brain barrier into the central nervoussystem (CNS), sequestration of the compound in the CNS as a result of invivo hydrolysis of an ester by esterases, modification of the half-lifeof the therapeutic compound, and any combination thereof.
 239. Themethod of claim 237, wherein the favorable biological property isselected from the group consisting of alteration of charge,pharmacology-kinetics, log P by a value of 1 or more, and anycombination thereof.
 240. The method of claim 237, wherein the favorablebiological property is selected from the group consisting of increasedreceptor selectivity, reduced peripheral half-life, the ability toincrease dosage, increased peripheral elimination, decreasedanti-muscarinic activity, decreased anti-cholinergic, or any combinationthereof, relative to the original AH compound.
 241. The method of claim237, wherein the FBP is the discrete period of time that the therapeuticcompound remains active in said subject.
 242. The method of claim 237,wherein the FBP is the induction of a discrete sleep or hypnotic state.243. The method of claim 237, wherein the FBP is the reduced ability ofthe subject to form a tolerance to the therapeutic compound.
 244. Themethod of claim 237, wherein the FBP is penetration through the bloodbrain barrier into the CNS.
 245. The method of claim 244, wherein theFBP is penetration through the blood brain barrier into the CNS due tothe lipophilicity of substituents or conformational lipophilicity. 246.The method of claim 245, wherein the conformational lipophilicity is aresult of an internal salt formation between a carboxylate anion on thetherapeutic compound and a protonated amine.
 247. The method of claim238, wherein the FBP is modulation of the half-life of the therapeuticcompound.
 248. The method of claim 240, wherein the favorable biologicalproperty of said AH compound is increased receptor selectivity relativeto the original AH compound.
 249. The method of claim 240, wherein thefavorable biological property of said AH compound is reduced peripheralhalf-life relative to the original AH compound.
 250. The method of claim240, wherein the favorable biological property of said AH compound isthe ability to increase dosage relative to the original AH compound.251. The method of claim 240, wherein the favorable biological propertyof said AH compound is increased peripheral elimination relative to theoriginal AH compound.
 252. The method of claim 237, wherein the DA ofsaid therapeutic compound is an acid, and has an FBP that includesincreased concentration within the CNS for a discrete period of time asa result of the existence of an ionic bond that includes the carboxylateion of the corresponding carboxylic acid.
 253. The method of claim 237,wherein the DA of said therapeutic compound is an ester and has an FBPthat includes increased concentration within the CNS for a discreteperiod of time as a result of a slower rate of conversion to thecorresponding carboxylic acid by in vivo esterase activity within theCNS as compared with the periphery.
 254. The method of claim 253,wherein said acid is not a therapeutically active agent for treatingdisorders.
 255. The method of claim 237, wherein the DA of said compoundis an ester or an alcohol, and is more active as a therapeutic agent fortreating disorders than said compound having an acid DA.
 256. The methodof claim 242, wherein the therapeutic compound induces a discrete sleepor hypnotic state by penetration into the Central Nervous System (CNS).257. The method of claim 233, wherein the sleep disorder is selectedfrom the group consisting of insomnia, hypersomnia, narcolepsy, sleepapnea syndromes, parasomnia, restless leg syndrome, and circadian rhythmabnormality.
 258. The method of claim 233, wherein the sleep disorder isinsomnia.
 259. The method of claim 233, wherein the sleep disorder ishypersomnia.
 260. The method of claim 233, wherein the sleep disorder isnarcolepsy.
 261. The method of claim 233, wherein the sleep disorder iscircadian rhythm abnormality.
 262. The method of claim 261, wherein thecircadian rhythm abnormality is selected from the group consisting ofjet lag, shift-work disorders, and delayed or advanced sleep phasesyndrome.
 263. The method of claim 233, wherein the (CH₂)_(m) spacermolecule is substituted with one or more substituents.
 264. The methodof claim 263, wherein the spacer molecule is disubstituted.
 265. Themethod of claim 264, wherein the spacer molecule isgeminally-dialkylated.
 266. The method of claim 265, wherein the spacermolecule is geminally-dimethylated.
 267. The method of claim 263,wherein the spacer molecule is singly substituted with a substituentother than a noncyclic alkyl group.
 268. The method of claim 263,wherein the spacer molecule is substituted with a heteroatom or a cyclicsubstituent.
 269. The method of claim 268, wherein the cyclicsubstituent is a cyclic alkyl or a cyclic ether.
 270. The method ofclaim 233, further comprising administering the therapeutic compound ina pharmaceutically acceptable vehicle.
 271. The method of claim 233,wherein said therapeutic compound is selected from the group consistingof:

wherein a is 0 through 5, b is 0 through 5, and R is H or any groupwhich imparts properties to the therapeutic compound to promotepenetration into the CNS and to modify the half-life of the compound.272. The method of claim 233, wherein said therapeutic compound is:

wherein d is 0 through 5, e is 0 through 4, the dashed line represents asingle or double bond, and R is H or any group which imparts propertiesto the therapeutic compound to promote penetration into the CNS and tomodify the half-life of the compound.
 273. The method of claim 233,wherein said therapeutic compound is:

wherein f is 0 through 5, the dashed line represents a single or doublebond, and R is H or any group which imparts properties to thetherapeutic compound to promote penetration into the CNS and to modifythe half-life of the compound.
 274. The method of claim 233, whereinsaid therapeutic compound is:

wherein the dashed line represents a single or double bond; R is H orany group which imparts properties to the therapeutic compound topromote penetration into the CNS and to modify the half-life of thecompound; R₁═H, OH, CH₂OH, CH₂CH₂OH; R₂═H, CH₃, CF₃, Cl, Br; and n is 1,2, or
 3. 275. The method of claim 274, wherein the (CH₂)_(n) spacermolecule to the carboxyl group is substituted with one or moresubstituents.
 276. The method of claim 275, wherein the spacer moleculeis disubstituted.
 277. The method of claim 275, wherein the spacermolecule is geminally-dialkylated.
 278. The method of claim 275, whereinthe spacer molecule is geminally-dimethylated.
 279. The method of claim275, wherein the spacer molecule is singly substituted with asubstituent other than a noncyclic alkyl group.
 280. The method of claim279, wherein the spacer molecule is substituted with a heteroatom or acyclic substituent.
 281. The method of claim 280, wherein the cyclicsubstituent is a cyclic alkyl or a cyclic ether.
 282. The method ofclaim 233, wherein said therapeutic compound is:

wherein c is 0 through 5, and R is H or any group which impartsproperties to the therapeutic compound to promote penetration into theCNS and to modify the half-life of the compound.
 283. The method ofclaim 271, wherein a is 0 or 1 and b is 0 or
 1. 284. The method of claim272, wherein d is 0 or 1 and e is 0 or
 1. 285. The method of claim 273,wherein f is 0 or
 1. 286. The method of claim 282, wherein c is 0 or 1.287. The method of claim 271, wherein R is selected from the groupconsisting of hydrocarbons and perfluorocarbons.
 288. The method ofclaim 287, wherein the hydrocarbons are selected from the groupconsisting of linear, branched, cyclic, aromatic, and a combination ofaliphatic and aromatic, which are optionally substituted with O, N, S,or halogens.
 289. The method of claim 287, wherein the hydrocarbonscontain from 1 to 10 carbons.
 290. The method of claim 271, wherein R isselected from the group consisting of a methyl, an ethyl, an n-propyl,an isopropyl, a cyclopropyl, a t-butyl, an isobutyl, a cyclopentyl, acyclohexyl, a cycloheptyl, and a benzyl group.
 291. A sleep disordertarget modulator having a formula selected from the group consisting of:

wherein a is 0 through 5, b is 0 through 5, and R is H or any groupwhich imparts properties to the therapeutic compound to promotepenetration into the CNS and to modify the half-life of the compound.292. A sleep disorder target modulator having the formula:

wherein d is 0 through 5, e is 0 through 4, the dashed line represents asingle or double bond, and R is H or any group which imparts propertiesto the therapeutic compound to promote penetration into the CNS and tomodify the half-life of the compound.
 293. A sleep disorder targetmodulator having the formula:

wherein f is 0 through 5, the dashed line represents a single or doublebond, and R is H or any group which imparts properties to thetherapeutic compound to promote penetration into the CNS and to modifythe half-life of the compound.
 294. A sleep disorder target modulatorhaving the formula:

wherein the dashed line represents a single or double bond; R is H orany group which imparts properties to the therapeutic compound topromote penetration into the CNS and to modify the half-life of thecompound; R₁═H, OH, CH₂OH, CH₂CH₂OH; R₂═H, CH₃, CF₃, Cl, Br; and n is 1,2, or
 3. 295. The method of claim 294, wherein the (CH₂)_(n) spacermolecule to the carboxyl group is substituted with one or moresubstituents.
 296. The method of claim 295, wherein the spacer moleculeis disubstituted.
 297. The method of claim 295, wherein the spacermolecule is geminally-dialkylated.
 298. The method of claim 295, whereinthe spacer molecule is geminally-dimethylated.
 299. The method of claim295, wherein the spacer molecule is singly substituted with asubstituent other than a noncyclic alkyl group.
 300. The method of claim299, wherein the spacer molecule is substituted with a heteroatom or acyclic substituent.
 301. The method of claim 300, wherein the cyclicsubstituent is a cyclic alkyl or a cyclic ether.
 302. A sleep disordertarget modulator having the formula:

wherein c is 0 through 5, and R is H or any group which impartsproperties to the therapeutic compound to promote penetration into theCNS and to modify the half-life of the compound.
 303. The sleep disordertarget modulator of claim 291, wherein a is 0 or 1 and b is 0 or
 1. 304.The sleep disorder target modulator of claim 292, wherein d is 0 or 1and e is 0 or
 1. 305. The sleep disorder target modulator of claim 293,wherein f is 0 or
 1. 306. The sleep disorder target modulator of claim302, wherein c is 0 or
 1. 307. The sleep disorder target modulator ofclaim 291, wherein R is selected from the group consisting ofhydrocarbons and perfluorocarbons.
 308. The sleep disorder targetmodulator of claim 307, wherein the hydrocarbons are selected from thegroup consisting of linear, branched, cyclic, aromatic, and acombination of aliphatic and aromatic, which are optionally substitutedwith O, N, S, or halogens.
 309. The sleep disorder target modulator ofclaim 307, wherein the hydrocarbons contain from 1 to 10 carbons. 310.The sleep disorder target modulator of claim 291, wherein R is selectedfrom the group consisting of a methyl, an ethyl, an n-propyl, anisopropyl, a cyclopropyl, a t-butyl, an isobutyl, a cyclopentyl, acyclohexyl, a cycloheptyl, and a benzyl group.
 311. The sleep disordertarget modulator of claim 294, wherein R₁ and R₂ are not both H when thealkylene spacer molecule is unsubstituted.
 312. The sleep disordertarget modulator of claim 294, with the proviso that the compound is nota compound of Formula VI when the alkylene spacer molecule isunsubstituted, and R₁ and R₂ are selected from the group consisting ofH, halogen CF₃, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy.
 313. The sleep disordertarget modulator of claim 294, wherein n is not 2 or 3 when the spacermolecule is unsubstituted.
 314. The sleep disorder target modulator ofclaim 291, wherein R is a bulky alkyl group.
 315. The sleep disordertarget modulator of claim 314, wherein the bulky alkyl group is a Type Balkyl of Table
 1. 316. The sleep disorder target modulator of claim 314,wherein the bulky alkyl group is a Type A alkyl of Table
 1. 317. A sleepdisorder target modulator selected from the compounds depicted in Table2 and Table
 3. 318. The method of claim 233, wherein the therapeuticcompound is selected from the group consisting of the compounds in Table2.
 319. The method of claim 233, wherein the therapeutic compound isselected from the group consisting of the compounds in Table 3.